PPAR-activating compound and pharmaceutical composition comprising the compound

ABSTRACT

A compound represented by the following formula (1):  
                 
Or a salt thereof; and therapeutic durgs containing the compound. The compound selectively activates PPARα.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a PPAR activating compound whichselectively activates, among peroxisome proliferator-activated receptors(PPARs), α-type PPAR (i.e., PPARα), and is useful as a drug forpreventing and/or treating pathological conditions includinghyperlipidemia, arteriosclerosis, diabetes, complications of diabetes,inflammation, and heart diseases. The invention also relates to apharmaceutical composition containing the compound.

2. Background Art

PPARs are known to form a family of nuclear receptors, and threesub-types thereof (α, γ, δ) have already been identified (Nature, 347,645-650, 1990; Cell, 68, pp. 879-887, 1992; Cell, 97, pp. 161-163, 1999;Biochim. Biophys. Acta., 1302, pp. 93-109, 1996; and Journal ofMedicinal Chemistry, 43, pp. 527-550, 2000).

Among the three sub-types, PPARα is expressed predominantly in the liverand is known to be activated by plasticizeres and/or fibrates, such asWy 14643, clofibrate, fenofibrate, bezafibrate, or gemfibrosil (Journalof the National Cancer Institute, 90, 1702-1709, 1998, Current Opinionin Lipidology, 10, pp. 245-257, 1999).

In mammals, activation of PPARα is known to promote 1 oxidation of fattyacids and lower the blood triglyceride level. In humans, activation ofPPARα decreases levels of blood lipids such as low-density lipoprotein(LDL) cholesterol and very low-density lipoprotein (VLDL) cholesterol.Thus, a PPARα-activator is useful as a drug for preventing and/ortreating a disease such as hyperlipidemia. In addition, thePPARα-activator is considered to be useful as a drug for preventingand/or treating pathological conditions such as arteriosclerosis due toincrease in the high density lipoprotein (HDL) cholesterol and thesuppression of VCAM-1 (one of cell adhesion molecules). Furthermore, thePPARα-activator is considered to be useful as a drug for preventingand/or treating pathological conditions such as diabetes, inflammatorydisease, and heart diseases (Journal of Atherosclerosis and Thrombosis,3, pp. 81-89, 1996; Current Pharmaceutical Design, 3, pp. 1-14, 1997;Current Opinion in Lipidology, 10, pp. 151-159, 1999; Current Opinion inLipidology, 10, pp. 245-257, 1999; The Lancet, 354, pp. 141-148, 1999;Journal of Medicinal Chemistry, 43, pp. 527-550, 2000; and Journal ofCardiovascular Risk, 8, pp. 195-201, 2001).

PPARγ, which is expressed predominantly in adipocytes, is known to playan important role in differentiating and proliferating adipocytes.Examples of known activators for PPARγ include thiazolidine derivativedrugs such as troglitazone, pioglitazone, and rosiglitazone. These drugsare known to induce differentiated adipocytes having reduced insulinsensitivity into small adipocytes having high insulin sensitivity, tothereby improve insulin resistance (Journal of Biological Chemistry,270, 12953-12956, 1995; Endocrinology, 137, pp. 4189-4195, 1996; TrendsEndocrinol. Metab., 10, pp. 9-13, 1999; and J. Clin. Invest., 101, pp.1354-1361, 1998). However, activation of PPARγ has been reported to haveadverse effects on human to increase fat and body weight and causingobesity (The Lancet, 349, pp. 952, 1997). Recently, it has also beenreported that antagonizing the PPARγ possibly improves insulinresistance (Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999; The Journalof Biological Chemistry, 275, pp. 1873-1877, 2000; and J. Clin. Invest.,108, 1001-1013, 2001).

PPARδ, which is present ubiquitously in the body, is known to take partin lipid metabolism. However, only a few high-selectivity PPARδactivators have been reported, and the biological significance of PPARδremains unclear. At present, the structures of PPARδ activators arereported in a wide range of literature (Diabetes, 46, 1319-1327, 1997;and Journal of Medicinal Chemistry, 43, pp. 527-550, 2000). In a recentreport, a PPARδ activator GW 501516 elevates HDL level in monkeys (Proc.Natl. Acad. Sci., 98, pp. 5306-5311, 2001). Moreover, adipocytes orskeletal muscle cells which are expresses activated PPARδ are reportedto promote burning of fat (Cell, 113, pp. 159-170, 2003). However, acompound F, a PPARδ activator, disclosed in WO 97/28149 has anunfavorable effect of accumulating lipids in human macrophages (Journalof Biological Chemistry, 276, pp. 44258-44265, 2001). In addition,experiments using PPARδ-deficient mice indicate that activation of PPARδinduces lipid accumulation (Proc. Natl. Acad. Sci., 99, pp. 303-308,2002). These phenomena represent two conflicting effects in terms of theprogress and alleviation of arteriosclerosis. Thus, the significance ofPPARδ on treatment of arteriosclerosis still remains unelucidated.

As described above, a PPARα-selective activator having low selectivityto PPARγ and to PPARδ is expected to be useful for preventing and/ortreating, without causing obesity or increase in body weight,pathological conditions such as hyperlipidemia, arteriosclerosis,diabetes, complications of diabetes, inflammation, and heart diseases.

WO 02/46176 discloses a PPAR activator having a structure represented bythe following formula:

(wherein each of R₁ and R₂ represents a hydrogen atom, a halogen atom, anitro group, a C1-C8 alkyl group, a C1-C8 alkoxy group, or a C6-C10 arylgroup, or R₁ and R₂, together with the carbon atoms to which they arebonded, may form a benzene ring; X represents an oxygen atom, a sulfuratom, —NR₀— (R₀ represents a hydrogen atom or a C1-C8 alkyl group), or—CH═CH—; G represents a single bond or a carbonyl group; R₃ represents aC1-C8 alkyl group, a C2-C8 alkenyl group, a C2-C8 alkynyl group, a C3-C7cycloalkyl group, a C1-C8 alkyl group substituted by a C3-C7 cycloalkylgroup, a C6-C10 aryl group, an arylalkyl group (formed of a C6-C10 arylmoiety, with an alkyl moiety having 1 to 8 carbon atoms), a heterocyclicgroup, or a heterocyclicalkyl group (containing an alkyl moiety having 1to 8 carbon atoms); n is an integer of 0 to 5; Y represents —CH₂—, acarbonyl group, or —CH═CH—; Z represents an oxygen atom or a sulfuratom; p represents an integer of 0 to 5; each of R₄ and R₅ represents ahydrogen atom or a C1-C8 alkyl group; and W represents a carboxyl group,a C2-C8 alkoxycarbonyl group, a sulfonic acid group, a phosphonic acidgroup, a cyano group, or a tetrazolyl group).

However, the compounds disclosed in WO 02/46176 act on any sub-type ofPPARs (i.e., PPARα, PPARγ, and PPARδ), and thus are not regarded asPPARα-selective activators.

SUMMARY OF THE INVENTION

The present inventors have carried out extensive studies in order toobtain a compound which selectively activates α-type PPAR among otherPPARs, and have found that a compound represented by the followingformula (1) selectively activates PPARα and is useful as a drug forpreventing and/or treating, without causing obesity or increase in bodyweight, pathological conditions including hyperlipidemia,arteriosclerosis, diabetes, complications of diabetes, inflammation, andheart diseases. The present invention has been accomplished on the basisof this finding.

Accordingly, the present invention provides a compound represented bythe following formula (1):

(wherein each of R₁ and R₂, which may be identical to or different fromeach other, represents a hydrogen atom, a methyl group, or an ethylgroup; each of R_(3a), R_(3b), R_(4a), and R_(4b), which may beidentical to or different from each other, represents a hydrogen atom, ahalogen atom, a nitro group, a hydroxyl group, a C₁₋₄ alkyl group, atrifluoromethyl group, a C₁₋₄ alkoxy group, a di-C₁₋₄ alkylamino group,a C₁₋₄ alkylsulfonyloxy group, a C₁₋₄ alkylsulfonyl group, a C₁₋₄alkylsulfinyl group, or a C₁₋₄ alkylthio group, or R_(3a) and R_(3b), orR_(4a) and R_(4b) may be linked together to form an alkylenedioxy group;X represents an oxygen atom, a sulfur atom, or N—R₅ (R₅ represents ahydrogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkylsulfonyl group, or a C₁₋₄alkyloxycarbonyl group); Y represents an oxygen atom, S(O)_(l) (l is anumber of 0 to 2), a carbonyl group, a carbonylamino group, anaminocarbonyl group, a sulfonylamino group, an aminosulfonyl group; Zrepresents CH or N; n is a number of 1 to 6; and m is a number of 2 to6) or a salt thereof.

The present invention also provides a drug comprising, as an activeingredient, a compound represented by the above formula (1) or a saltthereof.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by the above formula (1) or a saltthereof and a pharmacologically acceptable carrier.

The present invention also provides the use, for producing a drug, of acompound represented by the above formula (1) or a salt thereof.

The present invention also provides a method for treating a diseaseselected from the group consisting of hyperlipidemia, arteriosclerosis,diabetes, complications of diabetes, inflammation and heart diseases,which comprises administering an effective amount of a compoundrepresented by the above formula (1) or a salt thereof to a subject inneed.

The compounds of the present invention provide a selective activationeffect on PPARα among other PPARs and are useful as therapeutic drugsfor preventing and/or treating, without inviting increase in body weightor obesity, pathological conditions such as hyperlipidemia,arteriosclerosis, diabetes, complications of diabetes, inflammation, andheart diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows activation factor of the compound of Example 1 with respectto each isoform of PPARs.

DETAILED DESCRIPTION OF THE INVENTION

As is evident from the formula (1), the compounds of the presentinvention are characterized by having a structure where a group:

is bonded to a nitrogen atom. Until the present invention, the fact thata compound having the above described structure selectively activatesPPARα has remained unknown.

When R_(3a), R_(3b), R_(4a), or R_(4b) in formula (1) is a halogen atom,the halogen atom may be fluorine, chlorine, or bromine, with fluorineand chlorine being preferred.

When R_(3a), R_(3b), R_(4a), R_(4b), or R₅ is a C₁₋₄ alkyl group, thealkyl group may be methyl, ethyl, n-propyl, isopropyl, or butyl. Ofthese, methyl is particularly preferred.

When R_(3a), R_(3b), R_(4a), or R_(4b) is a C₁₋₄ alkoxy group, thealkoxy group may be methoxy, ethoxy, n-propoxy, isopropoxy, or butoxy.Of these, methoxy is particularly preferred.

When R_(3a), R_(3b), R_(4a), or R_(4b) is a di-C₁₋₄ alkylamino group,the dialkylamino group may be dimethylamino, diethylamino, ordiisopropylamino. Of these, dimethylamino is particularly preferred.

When R_(3a), R_(3b), R_(4a), or R_(4b) is a C₁₋₄ alkylsulfonyloxy group,the alkylsulfonyloxy group may be methylsulfonyloxy or ethylsulfonyloxy.Of these, methylsulfonyloxy is particularly preferred.

When R_(3a), R_(3b), R_(4a), R_(4b), or R₅ is a C₁₋₄ alkylsulfonylgroup, the alkylsulfonyl group may be methylsulfonyl or ethylsulfonyl.Of these, methylsulfonyl is particularly preferred.

When R_(3a), R_(3b), R_(4a), or R_(4b) is a C₁₋₄ alkylsulfinyl group,the alkylsulfinyl group may be methylsulfinyl or ethylsulfinyl. Ofthese, methylsulfinyl is particularly preferred.

When R_(3a), R_(3b), R_(4a), or R_(4b) is a C₁₋₄ alkylthio group, thealkylthio group may be methylthio or ethylthio. Of these, methylthio isparticularly preferred.

Examples of the alkylenedioxy group which is formed by linking R_(3a)with R_(3b) or by linking R_(4a) with R_(4b) include methylenedioxy andethylenedioxy. Of these, methylenedioxy is particularly preferred.

When R₅ is a C₁₋₄ alkyloxycarbonyl group, the alkyloxycarbonyl group maybe methyloxycarbonyl or ethyloxycarbonyl. Of these, methyloxycarbonyl isparticularly preferred.

In relation to R₁ and R₂, the following cases are particularlypreferred: they are both hydrogen atoms; they are both methyl groups;one is a methyl group and the other is a hydrogen atom; or one is anethyl group and the other is a hydrogen atom.

X represents an oxygen atom, a sulfur atom, or N—R₅, with an oxygen atombeing preferred. Y represents an oxygen atom, S(O)_(l), a carbonylgroup, a carbonylamino group, an aminocarbonyl group, a sulfonylaminogroup, or an aminosulfonyl group. Of these, an oxygen atom is preferred.Z represents CH or N, with CH being preferred. l is a number of 0 to 2,with a number of 2 being preferred. n is a number of 1 to 6, with anumber of 1 to 3 being preferred. m is a number of 2 to 6, with a numberof 2 to 4 being preferred, and 2 or 3 being particularly preferred.

Examples of the salts of the compounds represented by formula (1) of thepresent invention include alkali metal salts such as sodium salts andpotassium salts; alkaline earth metal salts such as calcium salts andmagnesium salts; organic base salts such as ammonium salts andtrialkylamine salts; mineral acid salts such as hydrochloric acid saltsand sulfuric acid salts; and organic acid salts such as acetic acidsalts.

The compound of the present invention may take the form of a solvatesuch as a hydrate or a geometrical (cis, trans) isomer or an opticalisomer. These isomers also fall within the scope of the presentinvention.

Among the compounds of the present invention, examples of compoundswhich are preferred due to their high PPARα selectivities include thefollowing compounds or salts thereof:

-   2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl)aminomethyl]phenoxy]butyric    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl)aminoethyl]phenoxy]butyric    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl)aminoethyl]phenoxy]butyric    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl)aminomethyl]phenoxy]propionic    acid,-   3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl)aminomethyl]phenoxyacetic    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl)aminomethyl]phenoxy]butyric    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl)aminomethyl)phenoxy)butyric    acid,-   2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl)aminomethyl]phenoxy]propionic    acid.

The compounds of the present invention can be obtained in accordancewith, for example, the following production methods described inreaction schemes A to G.(in the following schemes, R₁, R₂, R_(3a), R_(3b), R_(4a), R_(4b), m, n,X, Y, and Z have the same meanings as described above; R₆ represents asubstituent which can protect hydroxyl groups such as a C₁₋₄ alkyl groupand a trialkylsilyl group (see, for example, “Protective Groups inOrganic Synthesis (John Wiley & Sons, Inc.)”); R₇ represents a C₁₋₄alkyl group; R₃ represents R_(3a) and R_(3b); R₄ represents R_(4a) andR_(4b); and p is 1 or 2).

The production method represented by reaction scheme A includes thefollowing steps: A phenol compound (a) is reacted with2-haloalkylcarboxylic acid ester (b), to thereby produce an aldehydecompound (c); the aldehyde compound (c) is reacted with an aminecompound, followed by reduction; the thus-obtained amino compound (d) isreacted with 2-halobenzoxazole, to thereby produce an ester compound(e); and the ester compound (e) is subjected to hydrolysis, to therebyproduce the compound (1a) of the present invention.

The first step (A-1) proceeds as follows. A phenol compound (a) isdissolved in a solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF), dioxane, or acetonitrile. A necessary amount ofan inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate(Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such astriethylamine or diisopropylethylamine is added thereto. Further, anecessary amount of a 2-haloalkylcarboxylic acid ester (b) such as2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or2-bromopropionic acid ester is added, and the resultant mixture isallowed to react at a temperature between room temperature and aroundthe boiling point of the solvent under stirring for several hours to 24hours. The ester is appropriately selected from among tert-butyl esters,ethyl esters, methyl esters, etc.

In the second step (A-2), the aldehyde compound (c) is dissolved in asolvent such as 1,2-dichloroethane, chloroform, dichloromethane, DMF,THF, dioxane, or acetonitrile. Subsequently, a suitably selected aminecompound and an acid such as acetic acid are added, followed byreduction with a reducing agent such as sodium triacetoxyborohydride(NaBH(OAc)₃). The reaction is carried out by stirring the mixture undercooling or at room temperature for several hours to 24 hours (in aninert gas atmosphere, if necessary).

The third step (A-3) proceeds as follows. The starting amino compound(d) is dissolved in a solvent such as DMF, THF, dioxane, oracetonitrile. 2-Halobenzoxazole such as 2-chlorobenzoxazole is addedthereto in the presence of a necessary amount of an inorganic base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours (in an inert gasatmosphere, if necessary).

The fourth step (A-4) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali the starting compound, the ester is dissolved in a solvent suchas methanol, ethanol, or THF; a base such as lithium hydroxide, sodiumhydroxide, or potassium hydroxide, or an aqueous solution thereof isadded thereto; and the mixture is allowed to react for several hours to24 hours under cooling, or between room temperature and around theboiling point of the solvent. After completion of reaction, the reactionmixture is acidified by use of an acid such as hydrochloric acid. On theother hand, in the case where a tert-butyl ester or any ester that iseasily decomposed by an acid is the starting compound, the ester isdissolved in a solvent such as dichloromethane or chloroform, followedby addition of an acid such as trifluoroacetic acid, and the resultantmixture is stirred for several hours to 24 hours under cooling or atroom temperature.

The production method represented by reaction scheme B includes thefollowing steps: The starting carboxylic acid (f) is reacted with anamine, to thereby produce an amidophenol compound (g); the amidophenolcompound (g) is reacted with a 2-haloalkylcarboxylic acid ester (b), tothereby produce an amide compound (h); the amide compound (h) ischemically reduced to thereby produce a secondary amino compound (i);the secondary amino compound (i) is reacted with 2-halo-1,3-benzoazole,to thereby produce an ester compound (j); and the ester compound (j) issubjected to hydrolysis, to thereby produce the compound (1b) of thepresent invention.

The first step (B-1) proceeds as follows. The starting carboxylic acid(f) is dissolved in a solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF), dioxane, acetonitrile, or a mixture of solventssuitably selected therefrom. A suitably selected amine is dissolved inthe solvent, and a necessary amount of a condensing agent such asdicyclohexylcarbodiimide or water-soluble carbodiimide (WSC.HCl) (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl) is added to themixture under cooling. Subsequently, according to needs, a compound suchas 1-hydroxy-1H-benztriazole (HOBt) or dimethylaminopyridine is added.The resultant mixture is allowed to react at a temperature between roomtemperature and around the boiling point of the solvent for severalhours to 24 hours.

The second step (B-2) proceeds as follows. The phenol compound (g) isdissolved in a solvent such as DMF, THF, dioxane, or acetonitrile. Anecessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃or an organic base such as triethylamine or diisopropylethylamine isadded thereto. Subsequently, a necessary amount of a2-haloalkylcarboxylic acid ester such as 2-bromoisobutyric acid ester,2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added,and the resultant mixture is allowed to react at a temperature betweenroom temperature and around the boiling point of the solvent understirring for several hours to 24 hours. The ester is appropriatelyselected from among tert-butyl esters, ethyl esters, methyl esters, etc.

The third step (B-3) proceeds as follows. The starting amide compound(h) is dissolved in a solvent such as THF or dioxane. Subsequently, ifnecessary, in an inert gas atmosphere, a necessary amount of a reducingagent such as borane tetrahydrofuran complex (BH₃.THF) is added thereto,and the reaction mixture is stirred at room temperature or under heatingfor several hours to 24 hours.

The fourth step (B-4) proceeds as follows. The starting secondary aminocompound (i) is dissolved in a solvent such as DMF, THF, dioxane, oracetonitrile. 2-Halobenzoazole such as 2-chlorobenzoxazole is addedthereto in the presence of a necessary amount of an inorganic base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours (in an inert gasatmosphere, if necessary).

The fifth step (B-5) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali is the starting compound, the ester is dissolved in a solventsuch as methanol, ethanol, or THF; a base such as lithium hydroxide,sodium hydroxide, or potassium hydroxide, or an aqueous solution thereofis added thereto; and the mixture is allowed to react for several hoursto 24 hours under cooling, or between room temperature and around theboiling point of the solvent. After completion of reaction, the reactionmixture is acidified by use of an acid such as hydrochloric acid. On theother hand, in the case where a tert-butyl ester or any ester that iseasily decomposed by an acid is used in the second step, the resultantester compound which serves as the starting compound of the fifth stepis dissolved in a solvent such as dichloromethane or chloroform,followed by addition of an acid such as trifluoroacetic acid, and theresultant mixture is stirred for several hours to 24 hours under coolingor at room temperature.

The production method represented by reaction scheme C includes thefollowing steps: A carboxylic acid (k) is reacted with an amine, tothereby produce an amide compound (l); the hydroxyl-protective group isremoved from the amide compound (l), to thereby produce a phenolcompound (g); the phenol compound (g) is reacted with2-haloalkylcarboxylic acid ester; the resultant compound is reduced tothereby produce an amino compound (i); the amino compound (i) is reactedwith 2-halo-1,3-benzoazole; and the resultant compound is subjected tohydrolysis, to thereby produce the compound of the present invention.

The first step (C-1) proceeds as follows. The starting carboxylic acid(k) is dissolved in a solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF), dioxane, acetonitrile, or a mixture of solventssuitably selected therefrom. A suitably selected amine is dissolved inthe solvent, and a necessary amount of a reagent such asdicyclohexylcarbodiimide or WSC.HCl is added to the mixture undercooling. Subsequently, according to needes, a compound such as HOBt ordimethylaminopyridine is added. The resultant mixture is allowed toreact at a temperature between room temperature and around the boilingpoint of the solvent for several hours to 24 hours.

The second step (C-2) proceeds as follows. The amide compound (l)prepared in the first step is dissolved in a solvent such asdichloromethane, chloroform, or chlorobenzene. Thereafter, a Lewis acidsuch as boron tribromide or aluminum chloride is added thereto, and themixture is stirred under cooling or at around the boiling point of thesolvent for several hours to 24 hours. If R₆═H, the reaction in thesecond step is not required.

The third step (C-3) proceeds as follows. The phenol compound (g) isdissolved in a solvent such as DMF, THF, dioxane, or acetonitrile. Anecessary amount of an inorganic base such as potassium carbonate(K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate (Cs₂CO₃) or anorganic base such as triethylamine or diisopropylethylamine is addedthereto. Subsequently, a necessary amount of a 2-haloalkylcarboxylicacid ester such as 2-bromoisobutyric acid ester, 2-bromo-n-butyric acidester, or 2-bromopropionic acid ester is added, and the resultantmixture is allowed to react at a temperature between room temperatureand around the boiling point of the solvent under stirring for severalhours to 24 hours. The ester is appropriately selected from amongtert-butyl esters, ethyl esters, methyl esters, etc.

The fourth step (C-4) proceeds as follows. The starting amide compound(h) is dissolved in a solvent such as THF or dioxane. Subsequently, ifnecessary, in an inert gas atmosphere, a necessary amount of a reducingagent such as borane tetrahydrofuran complex (BH₃-THF) is added thereto,and the reaction mixture is stirred at room temperature or under heatingfor several hours to 24 hours.

The fifth step (C-5) proceeds as follows. The starting amino compound(i) is dissolved in a solvent such as DMF, THF, dioxane, oracetonitrile. 2-Halo-1,3-benzoazole such as 2-chlorobenzoxazole is addedthereto in the presence of a necessary amount of an inorganic base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours (in an inert gasatmosphere, if necessary).

The sixth step (C-6) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali is used as the starting compound, the ester is dissolved in asolvent such as methanol, ethanol, or THF; a base such as lithiumhydroxide, sodium hydroxide, or potassium hydroxide, or an aqueoussolution thereof is added thereto; and the mixture is allowed to reactfor several hours to 24 hours under cooling, or between room temperatureand around the boiling point of the solvent. After completion ofreaction, the reaction mixture is acidified by use of an acid such ashydrochloric acid. On the other hand, in the case where a tert-butylester or any ester that is easily decomposed by an acid is used as thestarting compound, the ester is dissolved in a solvent such asdichloromethane or chloroform, followed by an addition of an acid suchas trifluoroacetic acid, and the resultant mixture is stirred forseveral hours to 24 hours under cooling or at room temperature.

The production method represented by reaction scheme D includes thefollowing steps: A phenol compound (m) is reacted with a2-haloalkylcarboxylic acid ester, to thereby produce a cyano compound(n); the cyano compound (n) is reduced to thereby produce an aminocompound (o); the amino compound (o) is reacted with2-halo-1,3-benzoazole, to thereby produce an amino compound (p); and theamino compound (p) is reacted with a halide; and the reaction compoundis subjected to hydrolysis, to thereby produce the compound (1b) of thepresent invention.

The first step (D-1) proceeds as follows. A phenol compound (m) isdissolved in a solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF), dioxane, or acetonitrile. A necessary amount ofan inorganic base such as potassium carbonate (K₂CO₃), sodium carbonate(Na₂CO₃), or cesium carbonate (Cs₂CO₃) or an organic base such astriethylamine or diisopropylethylamine is added thereto. Subsequently, anecessary amount of a 2-haloalkylcarboxylic acid ester such as2-bromoisobutyric acid ester, 2-bromo-n-butyric acid ester, or2-bromopropionic acid ester is added, and the resultant mixture isallowed to react at a temperature between room temperature and aroundthe boiling point of the solvent under stirring for several hours to 24hours. The ester is appropriately selected from among tert-butyl esters,ethyl esters, methyl esters, etc.

The second step (D-2) proceeds as follows. The starting cyano compound(n) is dissolved in a solvent such as THF or dioxane. Subsequently, ifnecessary, in an inert gas atmosphere, a necessary amount of a reducingagent such as borane tetrahydrofuran complex (BH₃-THF) is added thereto,and the reaction mixture is stirred at room temperature or under heatingfor several hours to 24 hours.

The third step (D-3) proceeds as follows. The starting amino compound(O) is dissolved in a solvent such as DMF, THF, dioxane, oracetonitrile. 2-Halo-1,3-benzoazole such as 2-chlorobenzoxazole is addedthereto in the presence of a necessary amount of an inorganic base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours (in an inert gasatmosphere, if necessary).

The fourth step (D-4) proceeds as follows. The starting amino compound(p) is dissolved in an inert solvent such as DMF, THF, dioxane, oracetonitrile. A suitably selected halide is added thereto in thepresence of a necessary amount of an inorganic base such as K₂CO₃,Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours.

The fifth step (D-5) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali is used as the starting compound, the ester is dissolved in asolvent such as methanol, ethanol, or THF; a base such as lithiumhydroxide, sodium hydroxide, or potassium hydroxide, or an aqueoussolution thereof is added thereto; and the mixture is allowed to reactfor several hours to 24 hours under cooling, or between room temperatureand around the boiling point of the solvent. After completion ofreaction, the reaction mixture is acidified by use of an acid such ashydrochloric acid. On the other hand, in the case where a tert-butylester or any ester that is easily decomposed by an acid is used as thestarting compound, the ester is dissolved in a solvent such asdichloromethane or chloroform, followed by addition of an acid such astrifluoroacetic acid, and the resultant mixture is stirred for severalhours to 24 hours under cooling or at room temperature.

The production method represented by reaction scheme E includes thefollowing steps: The starting carboxylic acid (k) is reacted withammonia or an ammonium salt, to thereby produce an amide compound (q);the hydroxyl-protective group is removed from the amide compound (q), tothereby produce a phenol compound (r); the pnenol copmpound (r) isreacted with 2-haloalkylcarboxylic acid ester, to thereby produce anamide compound (S); the amide compound (s) is reduced to thereby producean amino compound (t); the amino compound (t) is reacted with2-halo-1,3-benzoazole, to thereby produce an amino compound (p); theamino compound (p) is reacted with a halide, to thereby produce an aminocompound (j); and the amino compound (j) is subjected to hydrolysis,whereby the compound (1b) of the present invention is obtained.

The first step (E-1) proceeds as follows. The starting carboxylic acid(k) is dissolved in a solvent such as N,N-dimethylformamide (DMF),tetrahydrofuran (THF), dioxane, acetonitrile, or a mixture of solventssuitably selected therefrom. An inorganic base such as potassiumcarbonate (K₂CO₃), sodium carbonate (Na₂CO₃), or cesium carbonate(Cs₂CO₃) or an organic base such as triethylamine,diisopropylethylamine, or pyridine is added thereto. An anhydride suchas ditert-butyl dicarbonate is added to the mixture, followed bystirring for several minutes to 3 hours under cooling or at roomtemperature. Ammonia or an ammonium salt (e.g., ammoniumhydrogencarbonate) is added thereto. The resultant mixture is stirredfor several hours to 24 hours under cooling or at room temperature.

The second step (E-2) proceeds as follows. The amide compound (q)prepared in the first step is dissolved in a solvent such asdichloromethane, chloroform, or chlorobenzene, as needed. Thereafter, aLewis acid such as boron tribromide or aluminum chloride is addedthereto, and the mixture is stirred under cooling or at around theboiling point of the solvent for several hours to 24 hours. If R₆H, thereaction in the second step is not required.

The third step (E-3) proceeds as follows. The phenol compound (r) isdissolved in a solvent such as DMF, THF, dioxane, or acetonitrile. Anecessary amount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃or an organic base such as triethylamine or diisopropylethylamine isadded thereto. Subsequently, a necessary amount of a2-haloalkylcarboxylic acid ester such as 2-bromoisobutyric acid ester,2-bromo-n-butyric acid ester, or 2-bromopropionic acid ester is added,and the resultant mixture is allowed to react at a temperature betweenroom temperature and around the boiling point of the solvent understirring for several hours to 24 hours. The ester is appropriatelyselected from among tert-butyl esters, ethyl esters, methyl esters, etc.

The fourth step (E-4) proceeds as follows. The starting amide compound(s) is dissolved in a solvent such as THF or dioxane. Subsequently, ifnecessary, in an inert gas atmosphere, a necessary amount of a reducingagent such as borane tetrahydrofuran complex (BH₃.THF) is added thereto,and the reaction mixture is stirred at room temperature or under heatingfor several hours to 24 hours.

The fifth step (E-5) proceeds as follows. The starting amino compound(t) is dissolved in a solvent such as DMF, THF, dioxane, oracetonitrile. 2-Halo-1,3-benzoazole such as 2-chlorobenzoxazole is addedthereto in the presence of a necessary amount of an inorganic base suchas K₂CO₃, Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours (in an inert gasatmosphere, if necessary).

The sixth step (E-6) proceeds as follows. The starting amino compound(p) is dissolved in an inert solvent such as DMF, THF, dioxane, oracetonitrile. A suitably selected halide is added thereto in thepresence of a necessary amount of an inorganic base such as K₂CO₃,Na₂CO₃, or Cs₂CO₃ or an organic base such as triethylamine ordiisopropylethylamine. The mixture is allowed to react at a temperaturebetween room temperature and around the boiling point of the solventunder stirring for several hours to 24 hours.

The seventh step (E-7) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali is used as the starting compound, the ester is dissolved in asolvent such as methanol, ethanol, or THF; a base such as lithiumhydroxide, sodium hydroxide, or potassium hydroxide, or an aqueoussolution thereof is added thereto; and the mixture is allowed to reactfor several hours to 24 hours under cooling, or between room temperatureand around the boiling point of the solvent. After completion ofreaction, the reaction mixture is acidified by use of an acid such ashydrochloric acid. On the other hand, in the case where a tert-butylester or any ester that is easily decomposed by an acid is used as thestarting compound, the ester is dissolved in a solvent such asdichloromethane or chloroform, followed by addition of an acid such astrifluoroacetic acid, and the resultant mixture is stirred for severalhours to 24 hours under cooling or at room temperature.

The production method represented by reaction scheme F includes thefollowing steps: The starting aldehyde compound (u) is reacted with anamine compound, followed by reduction; the thus-obtained amino compound(v) is reacted with 2-halo-1,3-benzoazole, to thereby produce thecompound (w); the hydroxyl-protective group is removed from the compound(w), to thereby produce a phenol compound (x); the phenol compound isreacted with 2-hydroxycarboxylic acid ester, to thereby produce acompound (j); and the compound (j) is subjected to hydrolysis, tothereby produce the compound (1b) of the present invention.

The first step (F-1) proceeds as follows. The starting aldehyde compound(u) is dissolved in a solvent such as 1,2-dichloroethane, chloroform,dichloromethane, N,N-dimethylformamide (DMF), tetrahydrofuran (THF),dioxane, or acetonitrile. Subsequently, a suitably selected aminecompound and an acid such as acetic acid are added, followed byreduction with a reducing agent such as sodium triacetoxyborohydride(NaBH(OAc)₃). The reaction is carried out by stirring the mixture undercooling or at room temperature for several hours to 24 hours (in aninert gas atmosphere, if necessary).

The second step (F-2) proceeds as follows. The amino compound (v)prepared in the first step is dissolved in a solvent such as DMF, THF,dioxane, or acetonitrile. 2-Halo-1,3-benzoazole such as2-chlorobenzoxazole is added thereto in the presence of a necessaryamount of an inorganic base such as K₂CO₃, Na₂CO₃, or Cs₂CO₃ or anorganic base such as triethylamine or diisopropylethylamine. The mixtureis allowed to react at a temperature between room temperature and aroundthe boiling point of the solvent under stirring for several hours to 24hours (in an inert gas atmosphere, if necessary).

The third step (F-3) proceeds as follows. In the case where an esterthat is easily hydrolyzed with an alkali such as an acetyl group is usedas the starting compound the ester is dissolved in a solvent such asmethanol, ethanol, or THF; a base such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, or potassium carbonate or an aqueoussolution thereof is added thereto; and the mixture is allowed to reactfor several hours to 24 hours under cooling or at a temperature betweenroom temperature and around the boiling point of the solvent. Aftercompletion of reaction, the reaction mixture is neutralized or acidifiedby use of an acid such as an aqueous ammonium chloride solution ordiluted hydrochloric acid. In the case where the ester is easilydecomposed by an acid, as in the case of an ester having a methoxymethylmoiety, the ester is dissolved in a solvent such as dichloromethane orchloroform, and an acid such as hydrochloric acid is added to thesolution, followed by stirring the mixture for several hours to 24 hoursunder cooling or at room temperature. In the case of a silyl group suchas tert-butyldimethylsilyl, the silyl group is dissolved in a solventsuch as THF, dioxane, acetonitrile, dichloromethane, or chloroform, anda fluoride compound such as tetrabutylammonium fluoride is added to thesolution, followed by stirring the mixture for several hours to 24 hoursat a temperature between room temperature and around the boilingtemperature of the solvent. In this case, the reaction may be performedby dissolving the the silyl group in a solvent such as DMF, ethanol, ormethanol, adding a base such as potassium carbonate, cesium carbonate,or lithium hydroxide to the solution, and stirring the mixture forseveral hours to 24 hours at a temperature between room temperature andaround the boiling point of the solvent.

The fourth step (F-4) proceeds as follows. The phenol compound (x)obtained in the third step and a 2-hydroxycarboxylic acid ester such astert-butyl 2-hydroxybutyrate or ethyl lactate are dissolved in a solventsuch as THF, dioxane, acetonitrile, or toluene. Under the Mitsunobureaction conditions, the solution is stirred at a temperature betweenroom temperature and around the boiling point of the solvent for severalhours to 24 hours. Alternatively, a 2-hydroxycarboxylic acid ester suchas tert-butyl 2-hydroxybutyrate or ethyl lactate is dissolved in asolvent such as THF, dioxane, acetonitrile, toluene, or DMF.Subsequently, an inorganic base or an organic base such as triethylamineor diisopropylethylamine is added thereto. Subsequently, sulfonylchloride such as methanesulfonyl chloride or p-toluenesulfonyl chlorideis added thereto. The resultant mixture and the phenol compound (x)produced in the third step are mixed together, and the resultant mixtureis stirred for several hours to 24 hours under ice-cooling or at atemperature between room temperature and around the boiling point of thesolvent. The ester is appropriately selected from among tert-butylesters, ethyl esters, methyl esters, etc.

The fifth step (F-5) proceeds as follows. In the case where a methylester, ethyl ester, or any ester that is easily hydrolyzed with analkali is used as the starting compound, the ester is dissolved in asolvent such as methanol, ethanol, or THF; a base such as lithiumhydroxide, sodium hydroxide, or potassium hydroxide, or an aqueoussolution thereof is added thereto; and the mixture is allowed to reactfor several hours to 24 hours under cooling or at a temperature betweenroom temperature and around the boiling point of the solvent. Aftercompletion of reaction, the reaction mixture is acidified by use of anacid such as hydrochloric acid. On the other hand, in the case where atert-butyl ester or any ester that is easily decomposed by an acid isused as the starting compound, the ester is dissolved in a solvent suchas dichloromethane or chloroform, followed by addition of an acid suchas trifluoroacetic acid, and the resultant mixture is stirred forseveral hours to 24 hours under cooling or at room temperature.

This synthesis route enables a successful synthesis of compounds (1b),even when R₆ is a hydrogen atom. In this case (R₆=H), the process in thethird step F-3 is not required.

The production method represented by reaction scheme G includes thefollowing steps: The compound (z) obtained in the course of reactionscheme A is oxidized; and the oxidized compound is subjected tohydrolysis, to thereby produce the compound (1c) of the presentinvention.

The first step (G-1) proceeds as follows. The compound (z) produced inthe fourth step of reaction scheme A is dissolved in a solvent such aschloroform or dichloromethane. Subsequently, the compound (z) isoxidized by use of an peroxide such as m-chloroperoxybenzoic acid orH₂O₂ under stirring for several hours to 24 hours under cooling or atroom temperature.

The second step (G-2) proceeds as follows. In the case of a methylester, an ethyl ester, or any ester that is easily hydrolyzed with analkali, the ester compound is dissolved in a solvent such as methanol,ethanol, or THF; a base such as lithium hydroxide, sodium hydroxide, orpotassium hydroxide, or an aqueous solution thereof is added thereto;and the mixture is allowed to react for several hours to 24 hours undercooling or at a temperature between room temperature and around theboiling point of the solvent. After completion of reaction, the reactionmixture is acidified by use of an acid such as hydrochloric acid. In thecase of a tert-butyl ester or any ester that is easily decomposed by anacid, the ester compound is dissolved in a solvent such asdichloromethane or chloroform, and an acid such as trifluoroacetic acidis added to the solution, followed by stirring the mixture for severalhours to 24 hours under cooling or at room temperature.

The compounds according to the present invention can be produced throughany of the aforementioned methods. The thus-obtained products may bepurified in accordance with needs through a customary purificationmethod such as recrystallization or column chromatography. The compoundsmay be converted to the aforementioned desired salts or solvates througha routine process, in accordance with needs.

As described in relation to the below-mentioned Test Example, thethus-produced compounds of the present invention exert a selectiveactivation effect on PPARα. Thus, these compounds are useful as a drugfor preventing and/or treating pathological conditions of mammals(including humans) such as hyperlipidemia, arteriosclerosis, diabetes,complications of diabetes (e.g., diabetic nephropathy), inflammation,and heart diseases, without causing increase in body weight or obesity.

The pharmaceutical of the present invention contains, as an activeingredient, the present compound (1) or a salt thereof. No particularlimitation is imposed on the form of administration, and theadministration form can be appropriately determined in accordance withthe purpose of treatment, and selected from among, for examples, peroralsolid forms, peroral liquid forms, injections, suppositories, externalpreparations, ophthalmic solutions, nasal drops, ear drops, and patches.These administration forms can be produced by mixing the activeingredient with a pharmacologically acceptable carrier and through anypreparation methods known in the art.

When an oral solid drug product is prepared, the present compound (1) ismixed with a diluent (and, if necessary, an additive such as a binder, adisintegrant, a lubricant, a coloring agent, a sweetening agent, or aflavoring agent), and the resultant mixture is processed through aroutine method, to thereby produce an oral solid drug product such astablets, granules, powder, or capsules. Such an additive may be anadditive generally employed in the art. Examples of the diluent includelactose, sodium chloride, glucose, starch, microcrystalline cellulose,and silicic acid; examples of the binder include water, ethanol,propanol, simple syrup, liquefied gelatin, hydroxypropyl cellulose,methyl cellulose, ethyl cellulose, shellac, calcium phosphate, andpolyvinyl pyrrolidone; examples of the disintegrant include agar powder,sodium hydrogencarbonate, sodium lauryl sulfate, and monoglycerylstearate; examples of the lubricant include purified talc, stearatesalt, borax, and polyethylene glycol; examples of the coloring agentinclude β-carotene, yellow iron sesquioxide, and caramel; and examplesof the sweetening agent include saccharose and orange peel.

When a liquid drug product for oral administration is prepared, thepresent compound (1) is mixed with an additive such as a sweeteningagent, a buffer, a stabilizer, or a preservative, and the resultantmixture is processed through a routine method, to thereby produce anorally administered liquid drug product such as internal solutionmedicine, syrup, or elixir. Such an additive may be an additivegenerally employed in the art. Examples of the sweetening agent includesaccharose; examples of the buffer include sodium citrate; examples ofthe stabilizer include tragacanth; and examples of the preservativeinclude p-hydroxybenzoate ester.

When an injection is prepared, the present compound (1) is mixed with anadditive such as a pH regulator, a stabilizer, or an isotonicity agent,and the resultant mixture is processed through a routine method, tothereby produce an injection such as a subcutaneous injection, anintramuscular injection, or an intraveneous injection. Such an additivemay be an additive generally employed in the art. Examples of the pHregulator include sodium phosphate; examples of the stabilizer includesodium pyrosulfite; and examples of the isotonicity agent include sodiumchloride.

When a suppository is prepared, the present compound (1) is mixed withan additive such as a carrier or a surfactant, and the resultant mixtureis processed through a routine method, to thereby produce a suppository.Such an additive may be an additive generally employed in the art.Examples of the carrier include polyethylene glycol and hard fat, andexamples of the surfactant include polysorbate 80.

When an external drug product is prepared, the present compound (1) ismixed with an additive such as a base, a water-soluble polymer, asolvent, a surfactant, or a preservative, and the resultant mixture isprocessed through a routine method, to thereby produce externalpreparations such as liquids or solutions, creams, gels, or ointments.Examples of the base include liquid paraffin, white Vaseline, andpurified lanolin; examples of the water-soluble polymer includecarboxyvinyl polymer; examples of the solvent include glycerol andwater; examples of the surfactant include polyoxyethylene fatty acidester; and examples of the preservative include p-hydroxybenzoate ester.

When an ophthalmic solution is prepared, the present compound (1) ismixed with an additive such as a pH regulator, a stabilizer, anisotonicity agent, or a preservative, and the resultant mixture isprocessed through a routine method, to thereby produce an ophthalmicsolution. Such an additive may be an additive generally employed in theart. Examples of the pH regulator include sodium phosphate; examples ofthe stabilizer include sodium pyrosulfite and EDTA; examples of theisotonicity agent include sodium chloride; and examples of thepreservative include chlorobutanol.

When a nasal drop is prepared, the present compound (1) is mixed with anadditive such as a pH regulator, a stabilizer, an isotonicity agent, ora preservative, and the resultant mixture is processed through a routinemethod, to thereby produce a nasal drop. Such an additive may be anadditive generally employed in the art. Examples of the pH regulatorinclude sodium phosphate; examples of the stabilizer include sodiumpyrosulfite and EDTA; examples of the isotonicity agent include sodiumchloride; and examples of the preservative include benzalkoniumchloride.

When an ear drop is prepared, the present compound (1) is mixed with anadditive such as a pH regulator, a buffer, a stabilizer, an isotonicityagent, or a preservative, and the resultant mixture is processed througha routine method, to thereby produce an ear drop. Such an additive maybe an additive generally employed in the art. Examples of the pHregulator and the buffer include sodium phosphate; examples of thestabilizer include sodium pyrosulfite and EDTA; examples of theisotonicity agent include sodium chloride; and examples of thepreservative include benzalkonium chloride.

When a patch is prepared, the present compound (1) is mixed with anadditive such as a tackifier, a solvent, a cross linking agent, or asurfactant, and the resultant mixture is processed through a routinemethod, to thereby produce a patch such as a hydrated patch or plasterpatch. Such an additive may be an additive generally employed in theart. Examples of the tackifier include partially neutralizedpoly(acrylic acid), sodium polyacrylate, poly(2-ethylhexylacrylate), andstyrene-isoprene-styrene block copolymer; examples of the solventinclude glycerol and water; examples of the cross linking agent includedihydroxyaluminum aminoacetate and dried aluminum hydroxide gel; andexamples of the surfactant include polyoxyethylene fatty acid ester.

The dose of the drug of the present invention differs depending on theage, body weight, and condition of the patient and the manner andfrequency of administration, etc. The daily dose of the present compound(1) for an adult is typically 1 to 1,000 mg, and the drug is preferablyadministered perorally or parenterally once a day or several times a dayin a divided manner.

EXAMPLES

The present invention will next be described in detail by way ofexamples, which should not be construed as limiting the invention.

Production Example 1 Synthesis of Ethyl 2-(3-formylphenoxy)butyrate

3-Hydroxybenzaldehyde (18.3 g, 0.150 mol) was dissolved inN,N-dimethylformamide (150 mL). Subsequently, potassium carbonate (22.80g, 0.165 mol), and then ethyl 2-bromobutyrate (29.26 g, 0.150 mol) wereadded thereto, and the resultant mixture was stirred overnight at 80° C.The temperature of the reaction mixture was returned to roomtemperature. Ethyl acetate was added. Washing was performed sequentiallywith water and brine, followed by drying over sodium sulfate. Thereaction mixture was subjected to filtration, concentration underreduced pressure, and purification by silica gel column chromatography(n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained(35.29 g, 0.149 mol, 99.6%).

¹H-NMR (400 MHz, CDCl₃) δ: 1.10 (t, J=7 Hz, 3H), 1.26 (t, J=7 Hz, 3H),1.99-2.06 (m, 2H), 4.23 (q, J=7 Hz, 2H), 4.65 (t, J=6 Hz, 1H), 7.17-7.22(m, 1H), 7.35 (s, 1H), 7.45-7.49 (m, 2H), 9.95 (s, 1H.

Production Example 2 Synthesis of Ethyl2-[3-[N-[3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyrate

Ethyl 2-(3-formylphenoxy)butyrate (5.0 g, 21.2 mmol) was dissolved in1,2-dichloroethane (20 mL). Subsequently, 3-(4-fluorophenoxy)propylamine(4.65 g, 27.5 mmol) was added thereto, and the resultant mixture wasstirred for 20 minutes. Subsequently, sodium triacetoxyborohydride (95%,7.1 g, 31.8 mmol) and small amount of acetic acid were added thereto,and the mixture was stirred overnight at room temperature. A saturatedaqueous sodium hydrogencarbonate solution was added thereto. Thereaction mixture was extracted with chloroform, and the organic layerwas washed with brine. The resultant mixture was subjected to dryingover anhydrous sodium sulfate, concentration under reduced pressure, andpurification by silica gel chromatography (chloroform/methanol=30/1),whereby the target compound was obtained (6.7 g, 81%).

¹H-NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H),1.93-2.01 (m, 4H), 2.80 (t, J=7 Hz, 2H), 3.77 (s, 2H), 4.00 (t, J=6 Hz,2H), 4.21 (q, J=7 Hz, 2H), 4.55 (t, J=6 Hz, 1H), 6.74-6.84 (m, 3H),6.89-6.98 (m, 4H), 7.21 (t, J=8 Hz, 1H).

Production Example 3 Synthesis of Ethyl2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyrate

Ethyl 2-[3-[N-[3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyrate(6.2 g, 15.9 mmol) was dissolved in N,N-dimethylformamide (10 mL), andN,N-diisopropylethylamine (3.1 g, 23.8 mmol) was added dropwise thereto.Subsequently, 2-chlorobenzoxazole (2.9 g, 19.0 mmol) was added thereto,and the resultant mixture was stirred for 15 minutes at roomtemperature, followed by stirring overnight at 50° C. Subsequently, asaturated aqueous sodium hydrogencarbonate solution was added thereto.The reaction mixture was extracted with ethyl acetate, and the organiclayer was washed with brine. The resultant mixture was subjected todrying over anhydrous sodium sulfate, concentration under reducedpressure, and purification by silica gel chromatography (n-hexane/ethylacetate=4/1), whereby the target compound was obtained (7.5 g, 93%).

¹H-NMR (400 MHz, CDCl₃) δ 1.05 (t, J=7 Hz, 3H), 1.17 (t, J=7 Hz, 3H),1.96 (quintet, J=7 Hz, 2H), 2.14 (quintet, J=6 Hz, 2H), 3.70 (t, J=7 Hz,2H), 4.00 (t, J=6 Hz, 2H), 4.12 (q, J=7 Hz, 2H), 4.51 (t, J=6 Hz, 1H),4.72 (d, J=16 Hz, 1H), 4.77 (d, J=16 Hz, 1H), 6.75-6.81 (m, 3H),6.86-7.00 (m, 4H), 7.01 (t, J=8 Hz, 1H), 7.17 (t, J=8 Hz, 1H), 7.19-7.23(m, 2H), 7.36 (d, J=7 Hz, 1H).

Example 1 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyricAcid

Ethyl2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyrate(7.3 g, 14.4 mmol) was dissolved in a methanol-tetrahydrofuran mixedsolvent (25 mL), and an aqueous solution of 2 mol/L sodium hydroxide(21.6 mL, 43.2 mmol) was added dropwise thereto. The resultant mixturewas stirred for 2 hours at 60° C. and subjected to concentration underreduced pressure. A saturated aqueous sodium hydrogencarbonate solutionwas added thereto. Subsequently, the reaction mixture was extracted withethyl acetate, and the organic layer was washed with brine. Theresultant mixture was subjected to drying over anhydrous sodium sulfate,concentration under reduced pressure, and purification by silica gelchromatography (chloroform/methanol=60/1), whereby the target compoundwas obtained (6.7 g, q.).

¹H-NMR (400 MHz, CDCl₃) δ 1.04 (t, J=7 Hz, 3H), 1.95 (quintet, J=7 Hz,2H), 2.04 (quintet, J=6 Hz, 2H), 3.56-3.64 (m, 2H), 3.87 (t, J=6 Hz,2H), 4.50 (t, J=6 Hz, 1H), 4.62 (d, J=16 Hz, 1H), 4.68 (d, J=16 Hz, 1H),6.73-6.93 (m, 7H), 6.99 (t, J=8 Hz, 1H), 7.10-7.20 (m, 3H), 7.34 (d, J=8Hz, 1H).

In a manner similar to that described in Example 1, the compounds ofExamples 2 through Example 30 were synthesized.

Example 2 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminomethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.09 (t, J=7 Hz, 3H), 2.00 (quintet, J=7 Hz,2H), 3.81 (m, 2H), 4.13 (t, J=5 Hz, 2H), 4.57 (t, J=7 Hz, 1H), 4.84 (d,J=6 Hz, 2H), 6.73 (d, J=9 Hz, 2H), 6.86 (d, J=8 Hz, 1H), 6.87 (s, 1H),6.92 (d, J=8 Hz, 1H), 7.02 (t, J=8 Hz, 1H), 7.13-7.25 (m, 5H), 7.36 (d,J=8 Hz, 1H).

Example 3 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl]aminomethyl]phenoxy]butyricAcid

¹H NMR (270 MHz, CDCl₃) δ 1.08 (t, J=8 Hz, 3H), 2.01 (quintet, J=7 Hz,2H), 3.78 (m, 2H), 4.08 (t, J=5 Hz, 2H), 4.56 (t, J=7 Hz, 1H), 4.81 (d,J=16 Hz, 1H), 4.88 (d, J=16 Hz, 1H), 6.69-6.78 (m, 2H), 6.82-6.96 (m,5H), 7.03 (t, J=8 Hz, 1H), 7.12-7.29 (m, 3H), 7.36 (d, J=8 Hz, 1H).

Example 4 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminomethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.59 (s, 6H), 3.74 (s, 3H), 3.78 (t, J=5 Hz,2H), 4.09 (t, J=5 Hz, 2H), 4.84 (s, 2H), 6.71-6.81 (m, 4H), 6.81-7.05(m, 5H), 7.10-7.25 (m, 2H), 7.35 (d, J=8 Hz, 1H).

Example 5 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.56 (s, 6H), 2.04 (quintet, J=7 Hz, 2H), 3.59(t, J=7 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 4.64 (s, 2H), 6.74-6.94 (m, 7H),6.99 (t, J=8 Hz, 1H), 7.11-7.19 (m, 3H), 7.36 (d, J=7 Hz, 1H).

Example 6 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.56 (s, 6H), 3.81 (t, J=5 Hz, 2H), 4.13 (t,J=5 Hz, 2H), 4.83 (s, 2H), 6.74 (d, J=9 Hz, 2H), 6.85 (d, J=8 Hz, 1H),6.89 (s, 1H), 6.96 (d, J=8 Hz, 1H), 7.02 (t, J=8 Hz, 1H), 7.13-7.25 (m,5H), 7.36 (d, J=7 Hz, 1H).

Example 7 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-2-(3-dimethylaminophenoxy)ethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

¹H NMR (400 MHz, CDCl₃) δ 1.58 (s, 6H), 3.11 (s, 6H), 3.96 (m, 2H), 4.11(m, 2H), 4.86 (s, 2H), 6.71-6.85 (m, 4H), 6.98 (d, J=8 Hz, 1H),7.09-7.37 (m, 6H), 7.49 (d, J=8 Hz, 1H).

Example 8 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methanesulfonyloxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.53 (s, 6H), 2.12 (br s, 2H), 3.09 (s, 3H),3.74 (t, J=7 Hz, 2H), 3.97 (t, J=6 Hz, 2H), 4.74 (s, 2H), 6.80-6.91 (m,5H), 7.11-7.26 (m, 6H), 7.44 (d, J=7 Hz, 1H).

Example 9 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]propionicAcid

¹H NMR (400 MHz, CDCl₃) δ 1.61 (d, J=7 Hz, 3H), 2.06 (quintet, J=6 Hz,2H), 3.61 (m, 2H), 3.92 (t, J=6 Hz, 2H), 4.60-4.73 (m, 3H), 6.80-6.95(m, 6H), 7.00 (t, J=7 Hz, 1H), 7.10-7.26 (m, 5H), 7.36 (d, J=7 Hz, 1H).

Example 10 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-3-(4-methanesulfonyloxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.58 (s, 6H), 2.15 (br s, 2H), 3.09 (s, 3H),3.80 (t, J=7 Hz, 2H), 4.00 (t, J=6 Hz, 2H), 4.79 (s, 2H), 6.83 (d, J=9Hz, 2H), 6.89 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz,2H), 7.21-7.29 (m, 2H), 7.31 (t, J=8 Hz, 1H), 7.54 (d, J=8 Hz, 1H),11.40 (br s, 1H).

Sodium2-[4-[[N-(benzoxazol-2-yl)-N-3-(4-methanesulfonyloxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionate

2-[4-[[N-(Benzoxazol-2-yl)-N-3-(4-methanesulfonyloxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicacid (5.96 g, 10.7 mmol) was dissolved in methanol. A solution of NaOMe(580 mg, 10.7 mmol) in methanol was added thereto at room temperature,and then the resultant mixture was stirred for 1 hour. Subsequently, thereaction mixture was subjected to concentration under reduced pressure,and n-hexane was added to the resultant concentrate. The thus-obtainedsolid was purified, whereby a white amorphous powder was obtained (5.2g, 84%).

¹H-NMR (400 MHz, CDCl₃) δ 1.61 (s, 6H), 2.03 (br s, 2H), 3.08 (s, 3H),3.56 (br s 2H), 3.88 (br s, 2H), 4.64 (s, 2H), 6.81-6.83 (m, 4H), 7.01(t, J=7 Hz, 1H), 7.08 (d, J=8 Hz, 2H), 7.14-1.18 (m, 4H), 7.46 (d, J=8Hz, 1H).

Example 11 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 460 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]-2-methylpropionate

¹H-NMR (400 MHz, CDCl₃) δ 1.36 (s, 6H), 2.80 (quintet, J=7 Hz, 2H), 3.64(t, J=7 Hz, 2H), 3.94 (t, J=6 Hz, 2H), 4.62 (s, 2H), 6.73 (d, J=8 Hz,1H), 6.82-6.86 (m, 4H), 6.89-6.96 (m, 2H), 7.04-7.15 (m, 3H), 7.21-7.26(m, 2H), 7.30 (d, J=8 Hz, 1H).

Example 12 Synthesis of3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxyacetic Acid

MS (m/z) 432 (M⁺).

Sodium3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxyacetate

¹H-NMR (400 MHz, CD₃OD) δ 2.09 (quintet, J=7 Hz, 2H), 3.69 (t, J=7 Hz,2H), 3.97 (t, J=6 Hz, 2H), 4.52 (s, 2H), 4.74 (s, 2H), 6.83-6.91 (m,6H), 6.99 (td, J=8, 1 Hz, 1H), 7.13 (td, J=8, 1 Hz, 1H), 7.18-7.27 (m,5H).

Example 13 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]butyricAcid

MS (m/z) 460 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]butyrate

¹H-NMR (400 MHz, DMSO-d₆) δ 0.90 (t, J=7 Hz, 3H), 1.67-1.75 (m, 2H),2.09-2.11 (m, 2H), 3.67 (t, J=7 Hz, 2H), 3.99-4.03 (m, 3H), 4.69 (s,2H), 6.65-6.75 (m, 3H), 6.90-7.00 (m, 4H), 7.13 (t, J=8 Hz, 2H),7.24-7.29 (m, 3H), 7.33 (d, J=7 Hz, 1H).

Example 14 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyricAcid

MS (m/z) 490 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyrate

¹H-NMR (400 MHz, CD₃OD) δ 1.03 (t, J=7 Hz, 3H), 1.87-1.92 (m, 2H), 2.09(quintet, J=6.6 Hz, 2H), 3.67-3.73 (m, 5H), 3.95 (t, J=6 Hz, 2H), 4.35(t, J=6 Hz, 1H), 4.74 (s, 2H), 6.78-6.90 (m, 7H), 7.00 (td, J=8, 1 Hz,1H), 7.14-7.27 (m, 4H).

Example 15 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 490 (M+).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionate

¹H-NMR (400 MHz, CDCl₃) δ 1.35 (s, 6H), 2.03 (quintet, J=7 Hz, 2H), 3.60(t, J=7 Hz, 2H), 3.70 (s, 3H), 3.87 (t, J=6 Hz, 2H), 4.59 (s, 2H),6.70-6.83 (m, 6H), 6.93 (t, J=8 Hz, 1H), 7.00-7.02 (m, 2H), 7.08 (t, J=8Hz, 1H), 7.13 (d, J=8 Hz, 1H), 7.29 (d, J=8 Hz, 1H).

Example 16 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 494 (M+), 496 (M⁺+2).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionate

¹H-NMR (400 MHz, DMSO-d₆) δ 1.35 (s, 6H), 2.08 (quintet, J=7 Hz, 2H),3.64 (t, J=7 Hz, 2H), 4.01 (t, J=6 Hz, 2H), 4.66 (s, 2H), 6.71 (d, J=8Hz, 1H), 6.72-6.76 (m, 2H), 6.94-7.00 (m, 3H), 7.08 (t, J=8 Hz, 1H),7.13 (t, J=8 Hz, 1H), 7.26-7.35 (m, 4H).

Example 17 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-3-(3-dimethylaminophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 489 (M⁺).

Sodium2-[4-[[N-(benzoxazol-2-yl)-N-3-(3-dimethylaminophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionate

¹H-NMR (400 MHz, CD₃OD) δ 1.52 (s, 6H), 2.05-2.08 (m, 2H), 2.87 (s, 6H),3.86 (t, J=5 Hz, 2H), 4.18 (t, J=5 Hz, 2H), 4.80 (s, 2H), 6.30-6.47 (m,3H), 6.84 (dd, J=7, 2 Hz, 2H), 7.03-7.09 (m, 2H), 7.15-7.31 (m, 5H).

Example 18 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]propionicAcid

MS (m/z) 432 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]propionate

¹H-NMR (400 MHz, DMSO-d₆) δ 1.46 (d, J=7 Hz, 3H), 3.87 (t, J=6 Hz, 2H),4.23 (t, J=6 Hz, 2H), 4.75-4.80 (m, 3H), 6.76 (dd, J=8, 2 Hz, 1H),6.88-6.93 (m, 4H), 7.02 (t, J=8 Hz, 1H), 7.16 (t, J=8 Hz, 1H), 7.24 (t,J=8 Hz, 1H), 7.28-7.32 (m, 4H), 7.40 (d, J=8 Hz, 1H).

Exsample 19 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(3-dimethylaminophenoxy)propyl]aminomethyl]phenoxy]propionicAcid

MS (m/z) 489 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-(3-dimethylaminophenoxy)propyl]aminomethyl]phenoxy]propionate

¹H-NMR (400 MHz, CDCl₃) δ 1.38 (d, J=7 Hz, 3H), 2.04-2.08 (m, 2H), 2.86(s, 6H), 3.60-3.65 (m, 2H), 3.93 (t, J=6 Hz, 2H), 4.51-4.55 (m, 1H),4.57 (d, J=16 Hz, 1H), 4.66 (d, J=16 Hz, 1H), 6.25-6.28 (m, 2H), 6.36(dd, J=11, 2 Hz, 1H), 6.70 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz, 2H), 6.94(t, J=8 Hz, 1H), 7.02-7.11 (m, 3H), 7.15 (d, J=8 Hz, 1H), 7.31 (d, J=8Hz, 1H).

Exsample 202-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]propionicAcid

MS (m/z) 476 (M⁺).

Sodium2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]propionate

¹H-NMR (400 MHz, CD₃OD) δ 1.50 (d, J=7 Hz, 3H), 2.09 (quintet, J=7 Hz,2H), 3.68-3.75 (m, 5H), 3.94 (t, J=6 Hz, 2H), 4.58 (q, J=7 Hz, 1H), 4.74(s, 2H), 6.78-6.87 (m, 7H), 7.00 (td, J=8, 1 Hz, 1H), 7.12-7.27 (m, 4H).

Example 21 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 446 (M+).

Example 22 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 446 (M⁺).

Example 23 Synthesis of2-[2-[[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 446 (M⁺).

Example 24 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminomethyl]phenoxy]butyricAcid

MS (m/z) 446 (M⁺).

Example 25 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-2-(3-dimethylaminophenoxy)ethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 489 (M⁺).

Example 26 Synthesis of2-[3-[[N-(Benzoxazol-2-yl)-N-3-(3-dimethylaminophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 503 (M⁺).

Example 27 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 476 (M⁺).

Example 28 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 490 (M⁺).

Example 29 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 480 (M⁺), 482 (M⁺+2).

Example 30 Synthesis of2-[4-[[N-(Benzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminomethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 494 (M⁺), 496 (M⁺+2).

Production Example 4 N-2-Phenoxyethyl-3-hydroxyphenylacetamide

3-Hydroxyphenylacetate (1.5 g, 9.88 mmol) was dissolved indichloromethane. WSC.HCl (2.82 g, 14.76 mmol) and 2-phenoxyethylamine(1.5 g, 10.95 mmol) were added thereto, and then the resultant mixturewas stirred for 4 hours at room temperature. After completion ofreaction, water was added to the reaction mixture. The resultant mixturewas extracted with chloroform, followed by washing with brine. Theresultant mixture was subjected to drying over anhydrous sodium sulfate,concentration under reduced pressure, and purification bychromatography, whereby 2.85 g, a stoichiometric amount, of the targetcompound was obtained as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 3.38 (s, 2H) 3.61 (q, J=5 Hz, 2H) 4.00 (t, J=5Hz, 2H), 5.97 (br, 1H), 6.72 (m, 4H), 6.96 (t, J=8 Hz, 1H), 7.26 (m,4H).

Production Example 5 Synthesis of tert-Butyl2-[3-(N-2-phenoxyethylaminocarbonylmethyl)phenoxy]propionate

N-2-Phenoxyethyl-3-hydroxyphenylacetoamide (1.4 g, 5.16 mmol) wasdissolved in acetonitrile (10 mL). tert-Butyl 2-bromopropionate (1.3 g,6.19 mmol) and potassium carbonate (1.07 g, 7.74 mmol) were addedthereto, and then the resultant mixture was stirred overnight at 80° C.After completion of reaction, the reaction mixture was subjected toconcentration under reduced pressure. Ethyl acetate was added thereto.The mixture was washed with water and brine and dried over anhydroussodium sulfate. The dried mixture was subjected to concentration underreduced pressure and purification by chromatography, whereby 1.14 g ofthe target compound was obtained as a pale yellow oil (yield 54%).

Production Example 6 Synthesis of tert-Butyl2-[3-[2-(N-2-phenoxyethyl)aminoethyl]phenoxy]propionate

tert-Butyl 2-[3-(2-phenoxyehtylaminocarbonylmethyl)phenoxy]propionate(1.14 g, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL) under argonatmosphere. The mixture was cooled to 0° C., and then a 1M borane-THFcomplex in THF solution (8.5 mL, 8.5 mmol) was added thereto. Theresultant mixture was stirred for 30 minutes, followed by stirring for 3hours at 50° C. After completion of reaction, the reaction mixture wasallowed to cool. Subsequently, methanol was added thereto and subjectedto concentration under reduced pressure. Subsequently, chloroform wasadded to the concentrate. The mixture was washed with water and brineand dried over anhydrous sodium sulfate. The dried mixture was subjectedto concentration under reduced pressure and purification bychromatography, whereby 940 mg of the target compound was obtained as acolorless oil (yield 85%).

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H,) 1.56 (d, J=7 Hz, 3H), 2.79 (t,J=7 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 3.01 (t, J=5 Hz, 2H), 4.05 (t, J=5Hz, 2H), 4.60 (q, J=7 Hz, 1H), 6.69 (dd, J=2, 8 Hz, 1H), 6.75 (s, 1H),6.82 (d, J=8 Hz, 1H), 6.92 (m, 3H), 7.18 (t, J=8 Hz, 1H), 7.26 (m, 2H).

Production Example 7 Synthesis of tert-Butyl2-[3-[2-[N-(benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]propionate

tert-Butyl 2-[3-[2-(N-2-phenoxyehtyl)aminoethyl]phenoxy]propionate (200mg, 0.519 mmol) was dissolved in N,N-dimethylformamide. Subsequently,2-chlorobenzoxazole (95 mg, 0.623 mmol) and diisopropylethylamine (0.1mL, 0.623 mmol) were added thereto, and the mixture was stirredovernight at 80° C. After completion of reaction, ethyl acetate wasadded. Washing was performed with water and brine, followed by dryingover magnesium sulfate. The reaction mixture was subjected toconcentration under reduced pressure, and purification bychromatography, whereby 266 mg, a stoichiometric amount, of the targetcompound was obtained as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H) 1.57 (d, J=8 Hz, 3H), 3.02 (t,J=8 Hz, 2H), 3.86 (m, 4H), 4.20 (t, J=5 Hz, 2H), 4.60 (q, J=7 Hz, 1H),6.69 (dd, J=2, 8 Hz, 1H), 6.91 (m, 6H), 7.18 (t, J=8 Hz, 1H), 7.26 (m,4H), 7.36 (d, J=8 Hz, 1H).

Example 31 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]propionicAcid

tert-Butyl2-[3-[2-[N-(benzoxazol-2-yl)-N-2-phenoxyehtyl]aminoethyl]phenoxy]propionate(266 mg, 0.530 mmol) was dissolved in dichloromethane (3 mL).Subsequently, trifluoroacetic acid (1 mL) was added thereto, and themixture was stirred for 1 hour at room temperature. After completion ofreaction, the reaction mixture was subjected to concentration underreduced pressure, and the residue was subjected to purification bypreparative TLC, whereby 115 mg of the target compound was obtained as ayellow oil (yield 54%).

¹H NMR (400 MHz, CDCl₃) δ 1.60 (d, J=7 Hz, 3H), 3.02 (t, J=6 Hz, 2H),3.68-4.19 (m, 6H), 4.60 (q, J=7 Hz, 1H), 6.58 (s, 1H), 6.79 (d, J=8 Hz,1H), 6.85 (d, J=8 Hz, 2H), 6.90-6.97 (m, 2H), 7.12 (t, J=8 Hz, 1H), 7.26(m, 5H), 7.44 (d, J=8 Hz, 1H).

In a manner similar to that described in Example 31, the compounds ofExamples 32 through Example 73 were synthesized.

Example 32 Synthesis of2-[3-[3-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminopropyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 474 (M⁺).

Example 33 Synthesis of2-[4-[3-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminopropyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 474 (M⁺).

Example 34 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 464 (M⁺).

Example 35 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.57 (d, J=7 Hz, 3H), 2.90 (t, J=7 Hz, 2H),3.64-3.80 (m, 6H), 4.65 (q, J=7 Hz, 1H), 6.67-7.12 (m, 11H).

Example 36 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 498 (M⁺), 500 (M⁺+2).

Example 37 Synthesis of2-[3-[2-[N-2-(4-Fluorphenoxy)ethyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]propionicAcid

¹H-NMR (400 MHz, CDCl₃) δ 1.50 (d, J=7 Hz, 3H), 2.84 (t, J=7 Hz, 2H),3.53-3.95 (m, 9H), 4.61 (q, J=7 Hz, 1H), 6.51 (dd, J=3, 9 Hz, 1H),6.63-6.92 (m, 7H), 7.02-7.30 (m, 3H).

Example 38 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]butyricAcid

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7 Hz, 3H), 2.01 (m, 4H), 2.87 (t,J=7 Hz, 2H), 3.45-3.74 (4H, m), 3.92 (t, J=6 Hz, 2H), 4.55 (t, J=6 Hz,1H), 6.77 (m, 2H), 6.85 (d, J=8 Hz, 2H), 6.90-7.26 (m, 8H), 7.33 (d, J=8Hz, 1H).

Example 39 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]butyricAcid

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=8 Hz, 3H), 2.00 (m, 4H), 2.91 (t,J=7 Hz, 2H), 3.49-3.74 (m, 4H), 3.95 (t, J=6 Hz, 2H), 4.56 (q, J=6 Hz,1H), 6.65-7.26 (m, 11H), 8.06 (d, J=7 Hz, 1H).

Example 40 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 508 (M⁺), 510 (M⁺+2).

Example 41 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]butyricAcid

¹H NMR (400 MHz, CDCl₃) δ 1.08 (t, J=7 Hz, 3H), 2.00 (m, 2H), 2.95 (t,J=7 Hz, 2H), 3.61 (m, 1H), 3.77-4.14 (m, 5H), 4.52 (q, J=6 Hz, 1H), 6.71(s, 1H), 6.80 (m, 2H), 6.85 (d, J=7 Hz, 1H), 6.92 (t, J=7 Hz, 1H), 7.04(t, J=8 Hz, 1H), 7.16-7.26 (m, 6H), 7.37 (d, J=8 Hz, 1H).

Example 42 Synthesis of2-[3-[2-[N-(5-Methoxybenzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 490 (M⁺).

Example 43 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]propionicAcid

¹H NMR (400 MHz, CDCl₃) δ 1.60 (d, J=7 Hz, 3H), 3.00 (t, J=7 Hz, 2H),3.70-4.18 (m, 6H), 4.67 (q, J=7 Hz, 1H), 6.62 (s, 1H), 6.79 (m, 2H),6.85 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 1H), 6.95 (t, J=7 Hz, 1H),7.10-7.30 (m, 5H).

Example 44 Synthesis of2-[3-[2-[N-(5-Methoxybenzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]propionicAcid

¹H NMR (400 MHz, CDCl₃) δ 1.59 (d, J=7 Hz, 3H), 3.00 (t, J=6 Hz, 2H),3.67 (m, 1H), 3.80 (s, 3H), 3.90-4.21 (m, 5H), 4.58 (q, J=7 Hz, 1H),6.49 (s, 1H), 6.72 (dd, J=2, 9 Hz, 1H), 6.79-6.98 (m, 6H), 7.09 (d, J=9Hz, 2H), 7.21-7.30 (m, 2H).

Example 45 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 490 (M⁺).

Example 46 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 508 (M⁺).

Example 47 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 524 (M⁺), 526 (M⁺+2).

Example 48 Synthesis of2-[3-[2-[N-(5-Methoxybenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 520 (M⁺).

Example 49 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminoethyl]phenoxy]butyricAcid

¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=8 Hz, 3H), 2.01 (m, 4H), 2.92 (m,2H), 3.49-3.74 (m, 7H), 3.91 (t, J=6 Hz, 2H), 4.56 (q, J=6 Hz, 1H),6.74-7.26 (m, 11H).

Example 50 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 492 (M⁺).

Example 51 Synthesis of2-[3-[2-[N-3-(4-Fluorophenoxy)propyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]butyricAcid

MS (m/z) 522 (M⁺).

Example 52 Synthesis of2-[3-[2-[N-3-(4-Chlorophenoxy)propyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]butyricAcid

MS (m/z) 538 (M⁺), 540 (M⁺+2).

Example 53 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminoethyl]phenoxy]butyricAcid

MS (m/z) 508 (M⁺), 510 (M⁺+2).

Example 54 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CD₃OD) δ 0.94 (t, J=7 Hz, 3H), 1.77-1.85 (m, 2H), 2.88(t, J=7 Hz, 2H), 3.71 (t, J=5 Hz, 2H), 3.74 (t, J=7 Hz, 2H), 4.03 (t,J=5 Hz, 2H), 4.45 (t, J=5 Hz, 1H), 6.61-7.19 (m, 12H).

Example 55 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CD₃OD) δ 0.94 (t, J=7 Hz, 3H), 1.77-1.87 (m, 2H), 2.89(t, J=7 Hz, 2H), 3.71-3.77 (m, 4H), 4.04 (t, J=5 Hz, 2H), 4.44 (t, J=6Hz, 1H), 6.61-7.14 (m, 11H).

Example 56 Synthesis of2-[3-[2-[N-2-(4-Chlorophenoxy)ethyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CD₃OD) δ 0.94 (t, J=7 Hz, 3H), 1.77-1.85 (m, 2H), 2.88(t, J=7 Hz, 2H), 3.68 (s, 3H), 3.70-3.74 (m, 4H), 4.02 (t, J=5 Hz, 2H),4.45 (t, J=6 Hz, 1H), 6.48-7.12 (m, 11H).

Example 57 Synthesis of2-[3-[2-[N-(Benzothiazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]butyricAcid

¹H-NMR (400 MHz, CD₃OD) δ 1.04 (t, J=7 Hz, 3H), 1.88-1.93 (m, 2H), 3.00(t, J=7 Hz, 2H), 3.80 (t, J=7 Hz, 2H), 3.84 (t, J=5 Hz, 2H), 4.15 (t,J=5 Hz, 2H), 4.53 (t, J=5 Hz, 1H), 6.74-7.63 (m, 12H).

Example 58 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 476 (M⁺).

Example 59 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 494 (M⁺).

Example 60 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 510 (M⁺), 512 (M⁺+2).

Example 61 Synthesis of2-[3-[2-[N-(5-Methoxybenzoxazol-2-yl)-N-2-(4-methoxyphenoxy)ethyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 506 (M⁺).

Example 62 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 460 (M⁺).

Example 63 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 478 (M⁺).

Example 64 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 494 (M⁺), 496 (M⁺+2).

Example 65 Synthesis of2-[3-[2-[N-(5-Methoxybenzoxazol-2-yl)-N-3-phenoxypropyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 490 (M⁺).

Example 66 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 494 (M⁺), 496 (M⁺+2).

Example 67 Synthesis of2-[3-[2-[N-3-(4-Chlorophenoxy)propyl-N-(5-fluorobenzoxazol-2-yl)]aminoethyl]phenoxy]propionicAcid

MS (m/z) 512 (M⁺), 514 (M⁺+2).

Example 68 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-3-(4-chlorophenoxy)propyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 528 (M⁺), 530 (M⁺+2), 532 (M⁺+4).

Example 69 Synthesis of2-[3-[2-[N-3-(4-Chlorophenoxy)propyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]propionicAcid

MS (m/z) 524 (M⁺), 526 (M⁺+2).

Example 70 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 478 (M⁺).

Example 71 Synthesis of2-[3-[2-[N-(5-Fluorobenzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 496 (M⁺).

Example 72 Synthesis of2-[3-[2-[N-(5-Chlorobenzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminoethyl]phenoxy]propionicAcid

MS (m/z) 512 (M⁺), 514 (M⁺+2).

Example 73 Synthesis of2-[3-[2-[N-3-(4-Fluorophenoxy)propyl-N-(5-methoxybenzoxazol-2-yl)]aminoethyl]phenoxy]propionicAcid

MS (m/z) 508 (M⁺).

Production Example 8 Synthesis ofN-(4-Chlorophenoxyethyl)-3-(2-methoxyphenyl)propanamide

3-(2-Methoxyphenyl)propionic acid (8.3 g, 46.2 mmol) was dissolved intetrahydrofuran (20 mL), and 4-chlorophenoxyethylamine (10.3 g, 60.0mmol) was added dropwise thereto at room temperature. Subsequently, asolution (10 mL) of WSC.HCl (11.5 g, 60.0 mmol) in methylene chloridewas slowly added dropwise thereto under ice-cooling, followed bystirring overnight. Under ice cooling, diluted hydrochloric acid wasadded dropwise thereto, followed by extraction with chloroform. Theorganic layer was washed with brine, and the resultant mixture wassubjected to drying over anhydrous sodium sulfate, concentration underreduced pressure, and purification by silica gel chromatography(chloroform/methanol=20/1), whereby the target compound was obtained(12.8 g, 83%).

¹H-NMR (400 MHz, CDCl₃) δ 2.50 (t, J=8 Hz, 2H), 2.95 (t, J=8 Hz, 2H),3.59-3.63 (m, 2H), 3.81 (s, 3H), 3.91 (t, J=5 Hz, 2H), 5.87 (br s, 1H),6.75-6.84 (m, 4H), 7.12 (d, J=7 Hz, 2H), 7.23 (d, J=9 Hz, 2H).

Production Example 9 Synthesis ofN-(4-Chlorophenoxyethyl)-3-(2-hydroxyphenyl)propanamide

N-(4-Chlorophenoxyethyl)-3-(2-methoxyphenyl)propanamide (12.8 g, 38.3mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, a1.0M-boron tribromide/methylene chloride solution (49.8 mL, 49.8 mmol)was slowly added dropwise thereto under ice-cooling, followed bystirring for 1 hour at room temperature. Subsequently, water was slowlyadded dropwise thereto under ice-cooling, followed by stirring for 30minutes. The resultant mixture was extracted with chloroform. Theorganic layer was washed with brine, and the resultant mixture wassubjected to drying over anhydrous sodium sulfate, concentration underreduced pressure, and purification by column chromatography(n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (11.6g, 95%).

¹H-NMR (400 MHz, CDCl₃) δ 2.64 (t, J=6 Hz, 2H), 2.92 (t, J=6 Hz, 2H,),3.61-3.65 (m, 2H), 3.94 (t, J=5 Hz, 2H), 5.99 (br s, 1H), 6.75 (d, J=9Hz, 2H), 6.82 (t, J=7 Hz, 1H), 6.88 (d, J=7 Hz, 1H), 7.04 (d, J=7 Hz,1H), 7.07 (t, J=7 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 8.66 (s, 1H).

Production Example 10 Synthesis of tert-Butyl2-[2-[2-[N-2-(4-chlorophenoxy)ethylaminocarbonyl]ethyl]phenoxy]-2-methylpropionate

N-(4-Chlorophenoxyethyl)-3-(2-hydroxyphenyl)propanamide (11.6 g, 36.3mmol) was dissolved in acetonitrile (15 mL), and potassium carbonate(15.0 g, 109 mmol) was added thereto. Subsequently, tert-butyl2-bromoisobutyrate (20.2 g, 90.7 mmol) was added thereto, followed bystirring for 4 days at 70° C. Subsequently, water was added thereto, andthe resultant mixture was extracted with ethyl acetate. The organiclayer was washed with brine, and the resultant mixture was subjected todrying over anhydrous sodium sulfate, concentration under reducedpressure, and purification by silica gel chromatography(chloroform/methanol=50/1), whereby the target compound was obtained(7.4 g, 44%).

Production Example 11 Synthesis of tert-Butyl2-[2-[3-[N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionate

tert-Butyl2-[2-[2-[2-(4-chlorophenoxy)ethylaminocarbonyl]ethyl]phenoxy]-2-methylpropionate(7.4 g, 16.0 mmol) was dissolved in tetrahydrofuran (5.0 mL).Subsequently, a 1.0M borane-tetrahydrofuran complex in tetrahydrofuransolution (32.0 mL, 32.0 mmol) was added dropwise at room temperature,and the mixture was stirred for three hours at 50° C. Concentratedhydrochloric acid was added under ice-cooling, and the mixture wasstirred for three hours at room temperature. Aqueous 80% ethylaminesolution was added dropwise under ice-cooling, and the mixture wasextracted with ethyl acetate. The organic layer was washed with brine,followed by drying over anhydrous sodium sulfate, concentration underreduced pressure, and purification by silica gel chromatography(chloroform/methanol=50/1), whereby the target compound was obtained(3.9 g, 54%).

¹H-NMR (400 MHz, CDCl₃) δ 1.40 (s, 9H), 1.58 (s, 6H), 1.83 (quintet, J=7Hz, 2H), 2.67 (t, J=8 Hz, 2H), 2.70 (t, J=7 Hz, 2H), 2.99 (t, J=5 Hz,2H), 4.03 (t, J=5 Hz, 2H), 6.68 (d, J=8 Hz, 1H), 6.82 (t, J=9 Hz, 2H),6.84-6.88 (m, 1H), 7.05 (t, J=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 7.22 (d,J=9 Hz, 2H).

Production Example 12 Synthesis of tert-Butyl2-[2-[3-[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionate

tert-Butyl2-[2-[3-[N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionate(3.9 g, 8.71 mmol) was dissolved in DMF (5.0 mL), anddiisopropylethylamine (1.4 g, 10.5 mmol) was added dropwise thereto.Subsequently, 2-chlorobenzoxazole (1.6 g, 10.5 mmol) was added dropwisethereto, and the mixture was stirred overnight at 70° C. Subsequently,water was added thereto, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, followed by dryingover anhydrous sodium sulfate. The dried mixture was subjected toconcentration under reduced pressure, and purification by silica gelchromatography (n-hexane/ethyl acetate=4/1), whereby the target compoundwas obtained (4.5 g, 90%).

¹H-NMR (400 MHz, CDCl₃) δ 1.37 (s, 9H), 1.57 (s, 6H), 2.02-2.10 (m, 2H),2.71 (t, J=8 Hz, 2H), 3.70 (t, J=8 Hz, 2H), 3.93 (t, J=6 Hz, 2H), 4.22(t, J=5 Hz, 2H), 6.68 (d, J=8 Hz, 1H), 6.78 (t, J=9 Hz, 2H), 6.87 (t,J=8 Hz, 1H), 7.00 (t, J=8 Hz, 1H), 7.04-7.22 (m, 3H), 7.20 (d, J=9 Hz,2H), 7.23 (d, J=8 Hz, 1H), 7.35 (d, J=8 Hz, 1H).

Example 74 Synthesis of2-[2-[3-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionicAcid

tert-Butyl2-[2-[3-[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionate(4.5 g, 7.87 mmol) was dissolved in methylene chloride (10.0 mL).Subsequently, 50%-trifluoroacetic acid/methylene chloride solution (6.8g) was added dropwise thereto, and the mixture was stirred for threehours at room temperature. The resultant mixture was subjected toconcentration under reduced pressure, toluene azeotrope, andpurification by silica gel chromatography (chloroform/methanol=50/1),whereby the target compound was obtained (3.3 g, 83%).

¹H-NMR (400 MHz, CDCl₃) δ 1.61 (s, 6H), 1.94-2.14 (br, 2H), 2.69 (t, J=8Hz, 2H), 3.64 (t, J=8 Hz, 2H), 3.85 (t, J=5 Hz, 2H), 4.09 (t, 5 Hz, 2H),6.70 (d, J=9 Hz, 2H), 6.81 (d, J=8 Hz, 1H), 6.89 (t, J=7 Hz, 1H), 7.00(t, J=7 Hz, 1H), 7.10-7.19 (m, 3H), 7.16 (d, J=9 Hz, 2H), 7.21 (d, J=8Hz, 1H), 7.35 (d, J=8 Hz, 1H).

Sodium2-[2-[3-[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionate

2-[2-[3-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminopropyl]phenoxy]-2-methylpropionicacid (3.2 g, 6.28 mmol) was dissolved in methanol. A solution of NaOMe(340 mg, 6.28 mmol) in methanol was added thereto at room temperature,and then the resultant mixture was stirred for 1 hour. Subsequently, thereaction mixture was subjected to concentration under reduced pressure,and n-hexane was added to the resultant concentrate. The thus-obtainedsolid was purified, whereby a white amorphous powder was obtained (2.7g, 81%).

¹H-NMR (400 MHz, CDCl₃) δ 1.35 (s, 6H), 1.80-2.00 (br, 2H), 2.48-2.60(br, 2H), 3.45-3.60 (br, 2H), 3.80 (br s, 2H), 4.05-4.13 (br, 2H), 6.70(d, J=9 Hz, 2H), 6.75-6.80 (m, 2H), 6.87-7.01 (m, 3H), 7.08 (t, J=8 Hz,1H), 7.13-7.18 (m, 1H), 7.14 (d, J=9 Hz, 2H), 7.28 (t, J=8 Hz, 1H) MS(FAB) m/z: 533[(M⁺+1)+2], 531 (M⁺+1).

In a manner similar to that described in Example 74, the compound ofExamples 75 was synthesized.

Example 75 Synthesis of2-[2-[3-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminopropyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 474 (M⁺).

Production Example 13 Synthesis of tert-Butyl2-[4-(cyanomethyl)phenoxy]-2-methylpropionate

4-Hydroxyphenylacetonitrile (13.3 g, 100 mmol) and potassium carbonate(20.73 g, 150 mmol) were added to dimethylformamide (75 mL).Subsequently, tert-butyl 2-bromoisobutyrate (50.41 mL, 250 mmol) wasadded thereto, and the mixture was stirred for 24 hours at 80° C. Thetemperature of the reaction mixture was returned to room temperature,and ethyl acetate was added thereto. Washing was performed sequentiallywith water and brine, followed by drying over sodium sulfate. Theresultant mixture was subjected to concentration under reduced pressureand purification by silica gel column chromatography (n-hexane/ethylacetate=7/1), whereby the target compound was obtained (18.62 g, 67.62mmol, 67.6%).

Production Example 14 Synthesis of tert-Butyl2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate

tert-Butyl 2-[4-(cyanomethyl)phenoxy]-2-methylpropionate (5.50 g, 20.0mmol) was dissolved in tetrahydrofuran (90 mL). Subsequently, in anitrogen atmosphere, borane-tetrahydrofuran complex in tetrahydrofuransolution [1.08M BH₃-THF in THF (92.6 mL, 100 mmol)] was added thereto,and the mixture was stirred for three hours at 50° C. Subsequently, 1Mhydrochloric acid was gradually added at 0° C., and the resultantmixture was stirred for one hour at room temperature. Thereafter, thereaction mixture was made basic with sodium carbonate. Tetrahydrofuranwas evaporated, and then chloroform was added. Washing was performedsequentially with water and brine, followed by drying over sodiumsulfate. The reaction mixture was subjected to concentration underreduced pressure and purification by silica gel column chromatography(chloroform/methanol=10/1), whereby the target compound was obtained(5.16 g, 13.02 mmol, 65.1%).

¹H NMR (400 MHz, CDCl₃) δ1.44 (s, 9H), 1.54 (s, 6H), 2.67 (t, J=7 Hz,2H), 2.92 (t, J=7 Hz, 2H), 6.86 (m, 2H), 7.09 (m, 2H,).

Production Example 15 Synthesis of tert-Butyl2-[4-[2-N-(benzoxazol-2-yl)aminoethyl]phenoxy]-2-methylpropionate

tert-Butyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropionate (290 mg, 1.04mmol) was dissolved in tetrahydrofuran (4 mL). Subsequently,diisopropylethylamine (272 μL, 1.56 mmol), and then 2-chlorobenzoxazole(145 μL, 1.25 mmol) were added thereto, and the mixture was stirredunder argon atmosphere for 15 hours at room temperature. Ethyl acetatewas added to the reaction mixture. Washing was performed sequentiallywith water and brine, followed by drying over sodium sulfate. Thereaction mixture was subjected to filtration, concentration underreduced pressure, and separation by silica gel column chromatography(n-hexane/ethyl acetate=10/1), whereby the target compound was obtained(367 mg, 0.925 mmol, 88.9%).

Production Example 16 Synthesis of tert-Butyl2-[4-[2-[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]-2-methylpropionate

tert-Butyl2-[4-[2-N-(benzoxazol-2-yl)aminoethyl]phenoxy]-2-methylpropionate (50mg, 0.126 mmol) was dissolved in acetonitrile (3 mL). Subsequently,cesium carbonate (62 mg, 0.189 mmol) and2-(4-chlorophenoxy)-1-bromoethane (59 mg, 0.252 mmol) were addedthereto, and the mixture was stirred for 14 hours at 70° C. Thetemperature of the mixture was returned to room temperature, and ethylacetate was added. The resultant mixture was sequentially washed withwater and brine, followed by drying over sodium sulfate. The mixture wassubjected to concentration under reduced pressure and purification bypreparative TLC (silica gel, n-hexane/ethyl acetate=10/1), whereby thetarget compound was obtained (26 mg, 0.0474 mmol, 37.6%).

Examples 76 Synthesis of2-[4-[2-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

tert-Butyl2-[4-[2-[N-(benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]-2-methylpropionate(26 mg, 0.0474 mmol) was dissolved in dichloromethane (6 mL).Subsequently, trifluoroacetic acid (0.5 mL) was added thereto, and themixture was stirred for 5 hours at room temperature. The mixture wassubjected to concentration under reduced pressure and toluene azeotrope.Thereafter, chloroform was added thereto, and the mixture wassequentially washed with water and brine, followed by drying over sodiumsulfate. The resultant mixture was subjected to concentration underreduced pressure and purification by preparative TLC (silica gel,chloroform/methanol=10/1), whereby the target compound was obtained (23mg, 0.0467 mmol, 98.5%).

MS (FAB) m/z: 495 (M⁺+1).

In a manner similar to that described in Example 76, the compounds ofExamples 77 through 79 were synthesized.

Example 77 Synthesis of2-[4-[2-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 460 (M⁺).

Example 78 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 460 (M⁺).

Example 79 Synthesis of2-[3-[2-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

MS (FAB) m/z: 495 (M⁺+1), 497[(M⁺+1)+2].

Production Example 17 Synthesis of 2-Methoxyphenylacetamide

2-Methoxyphenylacetic acid (10.0 g, 60.1 mmol) was dissolved inacetonitrile (15 mL). Subsequently, pyridine (2.84 g, 36.1 mmol) anddi-tert-butyl dicarbonate [Boc₂O (19.6 g, 90.2 mmol)] were addedthereto. The mixture was stirred for 10 minutes at room temperature, andthen ammonium hydrogencarbonate (7.1 g, 90.2 mmol) were added. Aftercompletion of reaction, the reaction mixture was concentrated underreduced pressure. Thereafter, the resultant concentrate was added towater, and the resultant mixture was extracted with chloroform, followedby washing sequentially with 1M hydrochloric acid and brine. Theresultant mixture was subjected to drying over magnesium sulfate andconcentration under reduced pressure. The resultant concentrate was usedin Production Example 18 without purification.

Production Example 18 Synthesis of 2-Hydroxyphenylacetamide

2-Methoxyphenyl acetamide (13.0 g, 78.6 mmol) was dissolved in methylenechloride (10.0 mL). Subsequently, 1.0M boron tribromide in methylenechloride solution (157 mL, 157 mmol) was slowly added dropwise underice-cooling, and the mixture was stirred for one hour at roomtemperature. Subsequently, water was slowly added thereto underice-cooling, and the mixture was stirred for 30 minutes. The mixture wasextracted with chloroform, followed by washing the organic layer withbrine, drying over anhydrous sodium sulfate. The reaction mixture wassubjected to concentration under reduced pressure and purification bycolumn chromatography (n-hexane/ethyl acetate=20/1), whereby a whitesolid was obtained (1.8 g, 11.9 mmol, 15%).

Production Example 19 Synthesis of tert-Butyl2-[2-(aminocarbonylmethyl)phenoxy]-2-methylpropionate

2-Hydroxyphenyl acetamide (1.2 g, 7.93 mmol) was dissolved inacetonitrile (10 mL), and potassium carbonate (5.5 g, 39.6 mmol) wasadded to the solution. Subsequently, to the mixture, tert-butyl2-bromoisobutyrate (8.9 g, 39.6 mmol) was added, followed by stirring at80° C. After completion of reaction, water was added to the mixture. Theresultant mixture was extracted with ethyl acetate, followed by washingthe organic layer with water. The mixture was subjected to drying oversodium sulfate, concentration under reduced pressure, and purificationby silica gel chromatography (chloroform/methanol=40/1), whereby thetarget compound was obtained (1.4 g, 4.87 mmol, 61%).

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.65 (s, 6H), 3.59 (s, 2H),6.10-6.35 (br, 2H), 6.75 (d, J=8 Hz, 1H), 6.94 (t, J=7 Hz, 1H), 7.17 (t,J=8 Hz, 1H), 7.25 (d, J=7 Hz, 1H).

Production Example 20 Synthesis of tert-Butyl2-[2-(2-aminoethyl)phenoxy]-2-methylpropionate

tert-Butyl 2-[2-(aminocarbonylmethyl)phenoxy]-2-methylpropionate (1.4 g,4.87 mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently,under nitrogen atmosphere, borane-THF complex in THF solution [1.0MBH₃-THF in THF (14.6 mL, 14.6 mmol)] was added thereto, the mixture wasstirred for three hours at 50° C. Thereafter, concentrated hydrochloricacid was gradually added thereto at 0° C. The resultant mixture wasstirred for one hour at room temperature and made basic with an aqueousethylamine solution. Ethyl acetate was added thereto. The mixture wassequentially washed with water and brine, followed by drying over sodiumsulfate. The mixture was subjected to concentration under reducedpressure and purification by silica gel column chromatography(chloroform/methanol=30/1), whereby the target compound was obtained(830 mg, 2.97 mmol, 61%).

¹H-NMR (400 MHz, CDCl₃) δ 1.43 (s, 9H), 1.65 (s, 6H), 2.09 (br s, 2H),2.79 (t, J=7 Hz, 2H), 2.97 (t, J=7 Hz, 2H), 6.69 (d, J=8 Hz, 1H), 6.88(t, J=7 Hz, 1H), 7.07 (d, J=8 Hz, 1H), 7.14 (d, J=7 Hz, 1H).

Production Example 21 Synthesis of tert-Butyl2-[2-[2-N-(benzoxazol-2-yl)aminoethyl]phenoxy]-2-methylpropionate

tert-Butyl 2-[2-(2-aminoethyl)phenoxy]-2-methylpropionate (762 mg, 2.73mmol) was dissolved in tetrahydrofuran (5.0 mL). Subsequently,diisopropylethylamine (422.6 mg, 3.27 mmol), and then2-chlorobenzoxazole (502.4 mg, 3.27 mmol) were added thereto, and themixture was stirred overnight at room temperature. Ethyl acetate wasadded to the reaction mixture. Washing was performed sequentially withwater and brine, followed by drying over sodium sulfate. Thereafter, thereaction mixture was subjected to filtration, concentration underreduced pressure, and purification by silica gel column chromatography(n-hexane/ethyl acetate=6/1), whereby the target compound was obtained(977 mg, 2.46 mmol, 90%).

Production Example 22 Synthesis of tert-Butyl2-[2-[2-[N-(benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]-2-methylpropionate

tert-Butyl2-[2-[2-(N-benzoxazol-2-yl)aminoethyl]phenoxy]-2-methylpropionate (157mg, 0.40 mmol) was dissolved in acetonitrile (3.0 mL). Subsequently,cesium carbonate (282 mg, 0.87 mmol) and 2-phenoxyethyl bromide (160 mg,0.80 mmol) were added thereto, and the mixture was stirred overnight at80° C. The temperature of the reaction mixture was returned to roomtemperature, and ethyl acetate was added. Washing was performedsequentially with water and brine, followed by drying over sodiumsulfate. The reaction mixture was subjected to concentration underreduced pressure and purification by silica gel column chromatography(n-hexane/ethyl acetate=4/1), whereby the target compound was obtained(85.3 mg, 0.17 mmol, 41%).

Production Example 80 Synthesis of2-[2-[2-[N-(Benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

tert-Butyl2-[2-[2-[N-(benzoxazol-2-yl)-N-2-phenoxyethyl]aminoethyl]phenoxy]-2-methylpropionate(85.3 mg, 0.17 mmol) was dissolved in methylene chloride (3.0 mL).Subsequently, 50% trifluoroacetic acid in methylene chloride solutionwas added thereto, and the mixture was stirred for three hours at roomtemperature. The resultant mixture was subjected to concentration underreduced pressure and toluene azeotrope. Chloroform was added to theresultant mixture, and washing was performed sequentially with water andbrine, followed by drying over sodium sulfate, concentration underreduced pressure, and purification by preparative TLC (silica gel,chloroform/methanol=20/1), whereby the target compound was obtained(63.5 mg, 0.14 mmol, 81%).

MS (m/z) 460 (M⁺).

In a manner similar to that described in Example 80, the compound ofExample 81 was synthesized.

Production Example 81 Synthesis of2-[2-[2-[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminoethyl]phenoxy]-2-methylpropionicAcid

MS (m/z) 494 (M⁺), 496 (M⁺+2).

Production Example 23 Synthesis of3-tert-Butyldimethylsilyloxybenzaldehyde

3-Hydroxybenzaldehyde (5.0 g, 40.9 mmol) was dissolved in acetonitrile(10.0 mL). Subsequently, potassium carbonate (11.3 g, 81.9 mmol), andthen tert-butyldimethylchlorosilane (7.4 g, 49.1 mmol) were addedthereto, and the resultant mixture was stirred at room temperature.After completion of reaction, ethyl acetate was added thereto, followedby washing sequentially with water and brine, and drying over anhydroussodium sulfate. The reaction mixture was subjected to filtration,concentration under reduced pressure, and purification by silica gelcolumn chromatography (n-hexane/ethyl acetate=20/1), whereby the targetcompound was obtained (9.1 g, 94%).

¹H-NMR (400 MHz, CDCl₃) δ 0.00 (s, 6H), 0.77 (s, 9H), 6.88 (d, J=8 Hz,1H), 7.10 (s, 1H), 7.18 (t, J=8 Hz, 1H), 7.25 (d, J=8 Hz, 1H), 9.73 (s,1H).

Production Example 24 Synthesis ofN-3-(4-Methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine

3-tert-Butyldimethylsilyloxybenzaldehyde (1.5 g, 6.34 mmol) wasdissolved in 1,2-dichloroethane (10.0 mL). Subsequently,3-(4-methoxyphenoxy)propylamine (1.5 g, 8.25 mmol) was added thereto,and the resultant mixture was stirred for 20 minutes. At roomtemperature, sodium triacetoxyborohydride (1.75 g, 8.25 mmol) and aceticacid (495 mg, 8.25 mmol) were added thereto, and the mixture was stirredovernight. A saturated aqueous sodium hydrogencarbonate solution wasadded thereto. The reaction mixture was extracted with chloroform, andthe organic layer was washed with brine. The resultant mixture wassubjected to drying over anhydrous sodium sulfate, concentration underreduced pressure, and purification by silica gel chromatography(chloroform/methanol=50/1), whereby the target compound was obtained(1.9 g, 78%).

¹H-NMR (400 MHz, CDCl₃) δ 0.00 (s, 6H), 0.73 (s, 9H), 1.81 (m, 2H), 2.66(br. s, 2H), 3.58 (s, 3H), 3.61 (s, 2H), 3.81 (t, J=6 Hz, 2H), 6.55 (d,J=7 Hz, 1H), 6.63 (br. s, 5H), 6.73 (d, J=7 Hz, 1H), 6.99 (t, J=7 Hz,1H).

Production Example 25 Synthesis ofN-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine

N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine(1.9 g, 5.0 mmol) was dissolved in N,N-dimethylformamide (3.0 mL).Subsequently, N,N-diisopropylethylamine (768 mg, 5.9 mmol) was addeddropwise thereto. To the solution, 2-chlorobenzoxazole (912 mg, 5.94mmol) was added. The mixture was stirred for 15 minutes at roomtemperature, and then stirred overnight at 70° C. The resultant mixturewas extracted with ethyl acetate, followed by washing the organic layerwith brine, drying over anhydrous sodium sulfate, and concentrationunder reduced pressure. The resultant mixture was subjected topurification by silica gel column chromatography (n-hexane/ethylacetate=10/1), whereby the target compound was obtained (1.9 g, 73%).

¹H NMR (400 MHz, CDCl₃) δ 0.05 (s, 9H), 0.85 (s, 6H), 2.04 (m, 2H), 3.60(t, J=7 Hz, 2H), 3.67 (s, 3H), 3.87 (t, J=6 Hz, 2H), 4.63 (s, 2H),6.65-6.80 (m, 7H), 6.91 (t, J=7 Hz, 1H), 7.05-7.09 (m, 2H), 7.12 (d, J=8Hz, 1H), 7.27 (d, J=8 Hz, 1H).

Production Example 26 Synthesis ofN-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl-3-hydroxybenzylamine

N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl-3-tert-butyldimethylsilyloxybenzylamine(1.9 g, 3.6 mmol) was dissolved in solvent mixture ofN,N-dimethylformamide/H₂O (10/1) (5.0 mL). Subsequently, cesiumcarbonate (1.2 g, 3.6 mmol) was added thereto. The mixture was stirredfor 3 hours at room temperature, followed by concentration under reducedpressure. Hydrochloric acid (1.0 mol/L) was added thereto. The resultantmixture was extracted with ethyl acetate, followed by washing theorganic layer with brine, drying over anhydrous sodium sulfate, andconcentration under reduced pressure. The resultant mixture wassubjected to purification by silica gel chromatography (n-hexane/ethylacetate=5/1), whereby the target compound was obtained (1.3 g, 89%).

¹H-NMR (400 MHz, CDCl₃) δ 1.98 (quintet, J=7 Hz, 2H), 3.37 (t, J=7 Hz,2H), 3.75 (s, 3H), 3.86 (t, J=6 Hz, 2H), 4.61 (s, 2H), 6.65-6.81 (m,7H), 6.90-7.13 (m, 5H).

Production Example 27 Synthesis of Ethyl(R)-2-[3-[[N-(benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]propionate

N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl-3-hydroxybenzylamine(244 mg, 0.6 mmol) was dissolved in toluene (5.0 mL). Subsequently,(S)-ethyl lactate (78.4 mg, 0.66 mmol) and triphenylphosphine (174 mg,0.66 mmol) were added thereto. Under argon atmosphere, a 40%diethylazodicarboxylate in toluene solution (289 mL, 0.66 mmol) wasslowly added thereto at 0° C., and the mixture was stirred at roomtemperature. After completion of reaction, the resultant mixture wassubjected to concentration under reduced pressure, followed by additionof water, extraction with ethyl acetate, and washing the organic layerwith brine. The mixture was dried over anhydrous sodium sulfate,followed by concentration under reduced pressure and purification bysilica gel chromatography (n-hexane/ethyl acetate=9/1), whereby thetarget compound was obtained (180 mg, 60%).

¹H-NMR (400 MHz, CDCl₃) δ 1.16 (t, J=7 Hz, 3H), 1.56 (d, J=7 Hz, 3H),2.12 (quintet, J=7 Hz, 2H), 3.67 (t, J=7 Hz, 2H), 3.74 (s, 3H), 3.94 (t,J=6 Hz, 2H), 4.07-4.18 (m, 2H), 4.68 (q, J=7 Hz, 1H), 4.72 (s, 2H), 6.75(d, J=8 Hz, 1H), 6.79 (s, 4H), 6.83 (br. s, 1H), 6.88 (d, J=8 Hz, 1H),6.99 (t, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 7.18-7.22 (m, 2H), 7.35 (d,J=8 Hz, 1H).

Example 82 Synthesis of(R)-2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]propionicAcid

Ethyl(R)-2-[3-[[N-(benzoxazol-2-yl)-N-(3-(4-methoxyphenoxy)propyl)aminomethyl]phenoxy]propionate(180 mg, 0.36 mmol) was dissolved in solvent mixture oftetrahydrofuran/H₂O (6/1) (4.0 mL). Subsequently, lithium hydroxide.H₂O(25.9 mg, 0.43 mmol) was added thereto, and the mixture was stirred forone hour at 0° C. Under ice-cooling, the resultant mixture was acidifiedwith aqueous 1M HCl solution, and then subjected to extraction withethyl acetate and sequentially washing with water and brine. The mixturewas dried over sodium sulfate, followed by concentration under reducedpressure and purification by silica gel column chromatography(chloroform/methanol=10/1), whereby the target compound was obtained(112 mg, 65%).

¹H NMR (400 MHz, CDCl₃) δ 1.40 (br s, 3H), 2.01 (m, 2H), 3.58 (t, J=7Hz, 2H), 3.70 (s, 3H), 3.84 (t, J=6 Hz, 2H), 4.55 (br s, 1H), 4.59 (s,2H), 6.70-6.81 (m, 7H), 6.93 (t, J=8 Hz, 1H), 7.03-7.14 (m, 3H), 7.31(d, J=8 Hz, 1H).

Also, the compounds shown in Tables 1 to 7 below have been synthesized.TABLE 1

Examples R₁ R₂ R_(3a) R_(3b) R_(4a) R_(4b) 83 Me H 5-MeSO₃ H H H 84 Et H5-MeSO₃ H H H 85 Me H 5-MeSO₂ H H H 86 Et H 5-MeSO₂ H H H 87 Me H H H4-MeSO₂ H 88 Et H H H 4-MeSO₂ H 89 Me Me 5-F H H H 90 Me Me 5-Cl H H H91 Me Me 5-MeO H H H 92 Me Me H H 4-F H 93 Me Me 5-F H 4-F H 94 Me Me5-Cl H 4-F H 95 Me Me 5-MeO H 4-F H 96 Et H 4-F H H H 97 Me H 4-F H H H98 Et H 5-F H H H 99 Me H 5-F H H H

TABLE 2 Examples R₁ R₂ R_(3a) R_(3b) R_(4a) R_(4b) 100 Et H 6-F H H H101 Me H 6-F H H H 102 Et H 7-F H H H 103 Me H 7-F H H H 104 Et H 4-F H4-F H 105 Me H 4-F H 4-F H 106 Et H 5-F H 4-F H 107 Me H 5-F H 4-F H 108Et H 6-F H 4-F H 109 Me H 6-F H 4-F H 110 Et H 7-F H 4-F H 111 Me H 7-FH 4-F H 112 Et H 4-F 6-F H H 113 Me H 4-F 6-F H H 114 Et H H H 3-NO₂ H115 Me H H H 3-NO₂ H 116 Et H H H 4-Me H 117 Me H H H 4-Me H 118 Et H5-CF₃ H 4-F H 119 Me H 5-CF₃ H 4-F H 120 Et H 5-CF₃ H H H 121 Me H 5-CF₃H H H 122 Et H 5-CH₃ H 4-F H 123 Me H 5-CH₃ H 4-F H 124 Et H 5-CH₃ H H H

TABLE 3 Examples R₁ R₂ R_(3a) R_(3b) R_(4a) R_(4b) 125 Me H 5-CH₃ H H H126 Et H H H 3,4-OCH₂O 127 Me H H H 3,4-OCH₂O 128 Et H 5,6-OCH₂O H H 129Me H 5,6-OCH₂O H H 130 Et H H H 2-Me 4-Me 131 Me H H H 2-Me 4-Me 132 EtH H H 3-Me 4-Me 133 Me H H H 3-Me 4-Me 134 Et H H H 2-F 4-F 135 Me H H H2-F 4-F 136 Et H H H 3-F 4-F 137 Me H H H 3-F 4-F

TABLE 4

Examples R₁ R₂ Y 138 Et H S 139 Me H S 140 Et H SO 141 Me H SO 142 Et HSO₂ 143 Me H SO₂ 144 Et H CO 145 Me H CO 146 Et H CONH 147 Me H CONH 148Et H NHCO 149 Me H NHCO 150 Et H SO₂NH 151 Me H SO₂NH 152 Et H NHSO₂ 153Me H NHSO₂ 154 Et H NH 155 Me H NH 156 Et H NMe 157 Me H NMe

TABLE 5

Exampls R₁ R₂ R_(4a) m 158 Et H H 2 159 Et H F 2 160 Et H Cl 2 161 Et HMeO 2 162 Me H H 2 163 Me H F 2 164 Me H Cl 2 165 Me H MeO 2 166 Et H H3 167 Et H F 3 168 Et H Cl 3 169 Et H MeO 3 170 Me H H 3 171 Me H F 3172 Me H Cl 3 173 Me H MeO 3

TABLE 6

Examples R₁ R₂ X 174 Et H NH 175 Me H NH 176 Et H N-SO₂Me 177 Me HN-SO₂Me

TABLE 7

Examples R₁ R₂ Pyridil 178 Et H 4-Py 179 Me H 4-Py 180 Et H 3-Py 181 MeH 3-Py 182 Et H 2-Py 183 Me H 2-Py

Test Example 1

PPAR activating effects of the compounds of the present inventionrepresented by formula (1) and comparative compounds disclosed in WO02/46176 (hereinafter referred to as compounds A, B, and C) weredetermined through the following method (Proc. Natl. Acad. Sci., 92, pp.7297-7301, 1995; Journal of Lipid Research, 40, pp. 2099-2110, 1999; andProc. Natl. Acad. Sci, 98, pp. 5306-5311, 2001).

(1) Measurement MethodsTransfection Assay

The COS-7 cell, which is an African green monkey kidney cell line, wasused for all transfection assays. Cells were cultured in DMEM mediumsupplemented with 10% fetal bovine serum, glutamic acid, and anantibiotic under humidified 5% CO₂ atmosphere.

The expression vector contained a DNA binding domain for Gal 4, which isa yeast transcription factor, and a binding domain for a ligand of humanPPAR. For each isoform of human PPAR, a vector was designed to containthe binding domain for the 1^(st)-147^(th) aa region of Gal 4transcription factor and; the 166^(th)-467^(th) aa region in the case ofPPARα 182^(nd)-505^(th) aa region in the case of PPARγ;137^(th)-441^(st) aa region in the case of PPARδ. The firefly luciferasewas used for reporter vector, which contained 5 base sequencesrecognizable by Gal 4 in its promorot region. Transections of cells withplasmids were carried out by lipfectamine and a β-galactosidaseexpression plasmid was used as an internal control for transfectionefficiency.

Transiently transfected cells were incubated in DMEM containing 0.2% FCSwith the compounds. And after 16 hours, luciferase activity andβ-galactosidase activity of cell lysate were measured.

Each compound was dissolved in and diluted with dimethyl sulfoxide(DMSO), and the DMSO concentration of the DMEM medium (containing 0.2%serum) was adjusted to 0.1% upon treatment of cells. The compoundsemployed for positive control are WY 14643, troglitazone (Journal ofMedicinal Chemistry, pp. 527-550, 2000), and GW 501516 (Proc. Natl.Acad. Sci., 98, pp. 5306-5311, 2001) for PPARα, PPARγ, and PPARδ,respectively.

Table 8 and 9 shows agonist activities for hPPARα, hPPARγ, hPPARδ. TABLE8 hPPAR; EC₅₀ (μM) Example No. α γ δ 1 0.01 >100 1.6 2 0.01 7.3 2.5 30.01 >100 1.8 6 0.07 3.5 >100 9 0.01 1.2 2.4 12 1.2 >100 >100 130.01 >50 2 14 0.0002 >100 1.7 15 0.05 >100 1.5 18 0.07 1.2 >100 190.0001 1.2 >100 20 0.01 1.2 2.0 24 0.03 1.4 2.3

TABLE 9 hPPAR; EC₅₀ (μM) Example No. α γ δ 31 0.09 >100 >50 34 0.06 1.21.6 35 0.02 1.2 1.6 36 0.05 2.1 1.6 37 0.07 4.2 1.5 38 0.05 1.5 1.4 390.08 9.1 1.6 41 0.04 2 >50 43 0.07 >100 5.3 44 0.08 >100 1.6 45 0.01 6.31.8 46 0.01 >100 1.8 47 0.04 >50 1.5 48 0.08 5.2 2 49 0.02 1.5 1.5 500.04 2.6 1.4 51 0.03 3.8 1.4 52 0.01 2 0.4 53 0.06 3.9 1.9 78 0.031.1 >100 Compound A 0.1 0.2 0.4 Compound B 0.12 0.7 0.9 Compound C — — —

The hPPARα selectivities of compounds A and B were found to be low, andspecifically, their levels are only less than 10-fold at EC₅₀ values ofhPPARγ and hPPARδ. In addition, compound C was found to exhibit noactivation of any hPPAR isoform. In contrast, the compounds of thepresent invention exhibited excellent hPPARα selectivity, clearlyrevealing that the compounds of the present invention have high hPPARαselectivity as compared with compounds A, B, and C disclosed in WO02/46176.

FIG. 1 show activation factors, with respect to each hPPAR isoform, ofthe compounds of the present invention (Examples 1) as determined atcorresponding EC₅₀ values in activation of hPPARα and at concentrations10 times those of EC₅₀ values. The activation factor is defined as aratio of activity of test compound to that of control, which containsonly the solvent (DMSO) and no test compound. As is clear from thisFIGURE, the compound of Example 1 exhibited substantially no activationof hPPARγ and hPPARδ even at the 10-fold concentration of EC₅₀ value inactivation of hPPARα. The results indicate that the compounds of thepresent invention can be used as excellent hPPARα-selective activators.

1. A compound represented by the following formula (1):

wherein each of R₁ and R₂, which may be identical to or different from each other, represents a hydrogen atom, a methyl group, or an ethyl group; each of R_(3a), R_(3b), R_(4a), and R_(4b), which may be identical to or different from each other, represents a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a C₁₋₄ alkyl group, a trifluoromethyl group, a C₁₋₄ alkoxy group, a C₁₋₄ alkylcarbonyloxy group, a di-C₁₋₄ alkylamino group, a C₁₋₄ alkylsulfonyloxy group, a C₁₋₄ alkylsulfonyl group, a C₁₋₄ alkylsulfinyl group, or a C₁₋₄ alkylthio group, or R_(3a) and R_(3b), or R_(4a) and R_(4b) may be linked together to form an alkylenedioxy group; X represents an oxygen atom, a sulfur atom, or N—R₅, wherein R₅ represents a hydrogen atom, a C₁₋₄ alkyl group, a C₁₋₄ alkylsulfonyl group, or a C₁₋₄ alkyloxycarbonyl group; Y represents an oxygen atom, S(O)_(l), wherein l is a number of 0 to 2, a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group, or NH; Z represents CH or N; n is a number of 1 to 6; and m is a number of 2 to 6or a salt thereof.
 2. The compound according to claim 1, wherein X represents an oxygen atom, Y represents an oxygen atom, and Z represents CH.
 3. A compound selected from the group consisting of 2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-fluorophenoxy)propyl]aminomethyl]phenoxy]butyric acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-chlorophenoxy)ethyl]aminomethyl]phenoxy]butyric acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-2-(4-fluorophenoxy)ethyl]aminomethyl]phenoxy]butyric acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]propionic acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]acetic acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-3-phenoxypropyl]aminomethyl]phenoxy]butyric acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]butyric acid, 2-[3-[[N-(Benzoxazol-2-yl)-N-3-(4-methoxyphenoxy)propyl]aminomethyl]phenoxy]propionic acid and a salt thereof.
 4. A drug comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 5. A therapeutic drug for hyperlipidemia comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 6. A therapeutic drug for arteriosclerosis comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 7. A therapeutic drug for diabetes comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 8. A therapeutic drug for complications of diabetes comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 9. A therapeutic drug for inflammation comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 10. A therapeutic drug for heart diseases comprising, as an active ingredient, a compound or a salt thereof as recited in any one of claims 1 through
 3. 11. A pharmaceutical composition comprising a compound or a salt thereof as recited in any one of claims 1 through 3 and a pharmacologically acceptable carrier.
 12. A method for treating pathological conditions selected from among hyperlipidemia, arteriosclerosis, diabetes, complications of diabetes, inflammation, and heart diseases, comprising administering to a subject in need thereof an effective amount of a compound or a salt thereof as recited in any one of claims 1 through
 3. 